{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T06:56:37Z","timestamp":1763535397404,"version":"build-2065373602"},"reference-count":187,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2016,5,13]],"date-time":"2016-05-13T00:00:00Z","timestamp":1463097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/69258\/2010","IF\/00732\/2013"],"award-info":[{"award-number":["SFRH\/BD\/69258\/2010","IF\/00732\/2013"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Among the tumor suppressor genes, p53 is one of the most studied. It is widely regarded as the \u201cguardian of the genome\u201d, playing a major role in carcinogenesis. In fact, direct inactivation of the TP53 gene occurs in more than 50% of malignancies, and in tumors that retain wild-type p53 status, its function is usually inactivated by overexpression of negative regulators (e.g., MDM2 and MDMX). Hence, restoring p53 function in cancer cells represents a valuable anticancer approach. In this review, we will present an updated overview of the most relevant small molecules developed to restore p53 function in cancer cells through inhibition of the p53-MDMs interaction, or direct targeting of wild-type p53 or mutated p53. In addition, optimization approaches used for the development of small molecules that have entered clinical trials will be presented.<\/jats:p>","DOI":"10.3390\/ph9020025","type":"journal-article","created":{"date-parts":[[2016,5,13]],"date-time":"2016-05-13T11:53:16Z","timestamp":1463140396000},"page":"25","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Chemical Variations on the p53 Reactivation Theme"],"prefix":"10.3390","volume":"9","author":[{"given":"Carlos","family":"Ribeiro","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"given":"Cec\u00edlia","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0727-9852","authenticated-orcid":false,"given":"Rui","family":"Moreira","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2239-9353","authenticated-orcid":false,"given":"Maria","family":"Santos","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2016,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nrc2723","article-title":"The first 30 years of p53: Growing ever more complex","volume":"9","author":"Levine","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nrc3711","article-title":"Unravelling mechanisms of p53-mediated tumour suppression","volume":"14","author":"Bieging","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1038\/nrc2763","article-title":"Awakening guardian angels: Drugging the p53 pathway","volume":"9","author":"Brown","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrm2147","article-title":"P53 in health and disease","volume":"8","author":"Vousden","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/nrc2716","article-title":"Tumour suppression by p53: A role for the DNA damage response?","volume":"9","author":"Meek","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1242\/jcs.064501","article-title":"p53 at a glance","volume":"123","author":"Brady","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.cell.2009.04.037","article-title":"Blinded by the light: The growing complexity of p53","volume":"137","author":"Vousden","year":"2009","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.cell.2007.02.022","article-title":"Wild-type p53: Tumors can\u2019t stand it","volume":"128","author":"Kastan","year":"2007","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/nature09535","article-title":"Stage-specific sensitivity to p53 restoration during lung cancer progression","volume":"468","author":"Feldser","year":"2010","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/ng1572","article-title":"Temporal dissection of p53 function in vitro and in vivo","volume":"37","author":"Christophorou","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1146\/annurev.pharmtox.48.113006.094723","article-title":"Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: A novel approach for cancer therapy","volume":"49","author":"Shangary","year":"2009","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/nrclinonc.2010.174","article-title":"Translating p53 into the clinic","volume":"8","author":"Cheok","year":"2011","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.semcancer.2010.02.006","article-title":"Therapeutic targeting of p53 by small molecules","volume":"20","author":"Selivanova","year":"2010","journal-title":"Semin. Cancer Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1593\/tlo.09250","article-title":"Targeting p53 for novel anticancer therapy","volume":"3","author":"Wang","year":"2010","journal-title":"Transl. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"631","DOI":"10.2174\/138161211795222595","article-title":"Pharmacological activation of p53 in cancer cells","volume":"17","author":"Athar","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1111\/j.2042-7158.2010.01248.x","article-title":"p53-targeted cancer pharmacotherapy: Move towards small molecule compounds","volume":"63","author":"Kim","year":"2011","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1111\/j.1476-5381.2011.01570.x","article-title":"Translational approaches targeting the p53 pathway for anti-cancer therapy","volume":"165","author":"Essmann","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1517\/14728222.2011.643299","article-title":"Targeting the p53 signaling pathway in cancer therapy\u2014The promises, challenges and perils","volume":"16","author":"Stegh","year":"2012","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.soc.2013.06.003","article-title":"Targeting the p53 pathway","volume":"22","author":"Golubovskaya","year":"2013","journal-title":"Surg. Oncol. Clin. N. Am."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/j.ctrv.2014.10.004","article-title":"p53 as a target for the treatment of cancer","volume":"40","author":"Duffy","year":"2014","journal-title":"Cancer Treat. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nrd4236","article-title":"Drugging the p53 pathway: Understanding the route to clinical efficacy","volume":"13","author":"Hoe","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"80","DOI":"10.2174\/1389450114666140106101412","article-title":"Targeting tumor suppressor p53 for cancer therapy: Strategies, challenges and opportunities","volume":"15","author":"Hong","year":"2014","journal-title":"Curr. Drug Targets"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1016\/j.febslet.2014.03.049","article-title":"Wild type p53 reactivation: From lab bench to clinic","volume":"588","author":"Selivanova","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1007\/s10495-014-0990-3","article-title":"Small molecule compounds targeting the p53 pathway: Are we finally making progress?","volume":"19","author":"Yu","year":"2014","journal-title":"Apoptosis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1111\/joim.12336","article-title":"Pharmacological reactivation of p53 as a strategy to treat cancer","volume":"277","author":"Selivanova","year":"2015","journal-title":"J. Intern. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1517\/14712598.2013.845662","article-title":"Advances in adenovirus-mediated p53 cancer gene therapy","volume":"13","author":"Tazawa","year":"2013","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1158\/1541-7786.20.2.1","article-title":"Inhibition of the p53-MDM2 interaction: Targeting a protein-protein interface","volume":"2","author":"Chene","year":"2004","journal-title":"Mol. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"57","DOI":"10.2174\/1568009053332672","article-title":"Small molecule antagonists of the MDM2 oncoprotein as anticancer agents","volume":"5","author":"Buolamwini","year":"2005","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"159","DOI":"10.2174\/1568026053507705","article-title":"Small molecule inhibitors of p53\/MDM2 interaction","volume":"5","author":"Fotouhi","year":"2005","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1517\/13543776.16.2.165","article-title":"Patented small molecule inhibitors of p53-MDM2 interaction","volume":"16","author":"Deng","year":"2006","journal-title":"Expert Opin. Ther. Patents"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s10989-006-9016-5","article-title":"Peptide, peptidomimetic, and small-molecule antagonists of the p53-HDM2 protein-protein interaction","volume":"12","author":"Fischer","year":"2006","journal-title":"Int. J. Pept. Res. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"952","DOI":"10.2174\/156802607780906762","article-title":"Small molecule protein-protein inhibitors for the p53-MDM2 interaction","volume":"7","author":"Dudkina","year":"2007","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1358\/dof.2007.032.10.1131965","article-title":"Inhibitors of the MDM2-p53 interaction as anticancer drugs","volume":"32","author":"Hardcastle","year":"2007","journal-title":"Drugs Future"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.molmed.2006.11.002","article-title":"MDM2 inhibitors for cancer therapy","volume":"13","author":"Vassilev","year":"2007","journal-title":"Trends Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.2174\/092986708784872375","article-title":"Small molecule inhibitors of the p53-MDM2","volume":"15","author":"Hu","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1517\/13543780802493366","article-title":"Small-molecule inhibitors of the p53-HDM2 interaction for the treatment of cancer","volume":"17","author":"Patel","year":"2008","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5318","DOI":"10.1158\/1078-0432.CCR-07-5136","article-title":"Targeting the MDM2-p53 interaction for cancer therapy","volume":"14","author":"Shangary","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.semcancer.2009.10.003","article-title":"Small-molecule inhibitors of MDM2 as new anticancer therapeutics","volume":"20","author":"Dickens","year":"2010","journal-title":"Semin. Cancer Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1517\/13543770903514129","article-title":"Patented inhibitors of p53-MDM2 interaction (2006\u20132008)","volume":"20","author":"Weber","year":"2010","journal-title":"Expert Opin. Ther. Patents"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"536","DOI":"10.2174\/138161211795222649","article-title":"Small-molecule inhibitors of p53-MDM2 interaction: The 2006\u20132010 update","volume":"17","author":"Millard","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"560","DOI":"10.2174\/138161211795222603","article-title":"Pharmacologic activation of p53 by small-molecule MDM2 antagonists","volume":"17","author":"Shen","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1517\/13543776.2012.656593","article-title":"p53-MDM2 inhibitors: Patent review (2009\u20132010)","volume":"22","author":"Kamal","year":"2012","journal-title":"Expert Opin. Ther. Patents"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4668","DOI":"10.2174\/138161212802651580","article-title":"p53 MDM2 inhibitors","volume":"18","author":"Khoury","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1016\/j.bmcl.2013.03.034","article-title":"Inhibitors of the p53\/HDM2 protein-protein interaction-path to the clinic","volume":"23","author":"Carry","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"553","DOI":"10.2174\/09298673113206660325","article-title":"Targeting MDM2-p53 interaction for cancer therapy: Are we there yet?","volume":"21","author":"Nag","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1021\/jm501092z","article-title":"Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 inhibitors) in clinical trials for cancer treatment","volume":"58","author":"Zhao","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1101\/gad.7.7a.1126","article-title":"The p53 MDM-2 autoregulatory feedback loop","volume":"7","author":"Wu","year":"1993","journal-title":"Genes Dev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1093\/abbs\/gmt147","article-title":"The regulation of MDM2 oncogene and its impact on human cancers","volume":"46","author":"Zhao","year":"2014","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1126\/science.274.5289.948","article-title":"Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain","volume":"274","author":"Kussie","year":"1996","journal-title":"Science"},{"key":"ref_50","unstructured":"ClinicalTrials.gov, Available online: http:\/\/clinicaltrials.gov\/."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1126\/science.1092472","article-title":"In vivo activation of the p53 pathway by small-molecule antagonists of MDM2","volume":"303","author":"Vassilev","year":"2004","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2680","DOI":"10.1002\/anie.201003863","article-title":"The structure-based design of MDM2\/MDMX-p53 inhibitors gets serious","volume":"50","author":"Popowicz","year":"2011","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3609","DOI":"10.1182\/blood-2005-04-1489","article-title":"Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma","volume":"106","author":"Stuhmer","year":"2005","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1073\/pnas.0507493103","article-title":"Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: Implications for therapy","volume":"103","author":"Tovar","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3380","DOI":"10.1158\/1078-0432.CCR-06-2581","article-title":"Inhibition of p53-murine double minute 2 interaction by nutlin-3a stabilizes p53 and induces cell cycle arrest and apoptosis in hodgkin lymphoma","volume":"13","author":"Drakos","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/leu.2008.11","article-title":"MDM2 antagonist nutlin-3 is a potent inducer of apoptosis in pediatric acute lymphoblastic leukemia cells with wild-type p53 and overexpression of MDM2","volume":"22","author":"Gu","year":"2008","journal-title":"Leukemia"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1007\/s00432-010-0817-8","article-title":"Nutlin-3 cooperates with doxorubicin to induce apoptosis of human hepatocellular carcinoma cells through p53 or p73 signaling pathways","volume":"136","author":"Zheng","year":"2010","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Ohnstad, H.O., Paulsen, E.B., Noordhuis, P., Berg, M., Lothe, R.A., Vassilev, L.T., and Myklebost, O. (2011). MDM2 antagonist nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines. BMC Cancer, 11.","DOI":"10.1186\/1471-2407-11-211"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1021\/ml4000657","article-title":"Discovery of rg7112: A small-molecule MDM2 inhibitor in clinical development","volume":"4","author":"Vu","year":"2013","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/S1470-2045(12)70474-6","article-title":"Effect of the MDM2 antagonist RG7112 on the p53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: An exploratory proof-of-mechanism study","volume":"13","author":"Blay","year":"2012","journal-title":"Lancet Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.1158\/0008-5472.CAN-12-2807","article-title":"MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models","volume":"73","author":"Tovar","year":"2013","journal-title":"Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5454","DOI":"10.1016\/j.bmc.2011.07.050","article-title":"Design, synthesis, and biological evaluation of imidazoline derivatives as p53-MDM2 binding inhibitors","volume":"19","author":"Hu","year":"2011","journal-title":"Bioorg. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/j.bmc.2012.01.003","article-title":"Design, synthesis and CoMFA studies of N1-amino acid substituted 2,4,5-triphenyl imidazoline derivatives as p53-MDM2 binding inhibitors","volume":"20","author":"Hu","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1517\/13543776.2012.727397","article-title":"Imidazoline derivatives: A patent review (2006\u2013present)","volume":"22","author":"Guan","year":"2012","journal-title":"Expert Opin. Ther. Patents"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1517\/13543776.2013.765405","article-title":"MDM2 and MDMX inhibitors for the treatment of cancer: A patent review (2011\u2013present)","volume":"23","author":"Zak","year":"2013","journal-title":"Expert Opin. Ther. Patents"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6338","DOI":"10.1016\/j.bmcl.2012.08.086","article-title":"Discovery of novel dihydroimidazothiazole derivatives as p53-MDM2 protein-protein interaction inhibitors: Synthesis, biological evaluation and structure-activity relationships","volume":"22","author":"Miyazaki","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1016\/j.bmc.2015.03.069","article-title":"Discovery of DS-5272 as a promising candidate: A potent and orally active p53-MDM2 interaction inhibitor","volume":"23","author":"Miyazaki","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1021\/jm049137g","article-title":"Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells","volume":"48","author":"Grasberger","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.bmcl.2004.11.009","article-title":"1,4-benzodiazepine-2,5-diones as small molecule antagonists of the HDM2-p53 interaction: Discovery and sar","volume":"15","author":"Parks","year":"2005","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/j.1747-0285.2006.00365.x","article-title":"Substituted 1,4-benzodiazepine-2,5-diones as alpha-helix mimetic antagonists of the HDM2-p53 protein-protein interaction","volume":"67","author":"Cummings","year":"2006","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"5061","DOI":"10.1021\/jm100112j","article-title":"A medicinal chemist\u2019s guide to molecular interactions","volume":"53","author":"Bissantz","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1016\/j.bmcl.2005.02.018","article-title":"Structure-based design, synthesis, and biological evaluation of novel 1,4-diazepines as HDM2 antagonists","volume":"15","author":"Raboisson","year":"2005","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3310","DOI":"10.1016\/j.bmcl.2006.03.055","article-title":"Enhanced pharmacokinetic properties of 1,4-benzodiazepine-2,5-dione antagonists of the HDM2-p53 protein-protein interaction through structure-based drug design","volume":"16","author":"Parks","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3463","DOI":"10.1016\/j.bmcl.2006.04.009","article-title":"Novel 1,4-benzodiazepine-2,5-diones as HDM2 antagonists with improved cellular activity","volume":"16","author":"Leonard","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1016\/j.bmcl.2006.03.067","article-title":"Enantiomerically pure 1,4-benzodiazepine-2,5-diones as HDM2 antagonists","volume":"16","author":"Marugan","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1158\/1535-7163.MCT-05-0199","article-title":"Benzodiazepinedione inhibitors of the HDM2: P53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo","volume":"5","author":"Koblish","year":"2006","journal-title":"Mol. Cancer Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/j.1747-0285.2010.00989.x","article-title":"1,4-thienodiazepine-2,5-diones via MCR (I): Synthesis, virtual space and p53-MDM2 activity","volume":"76","author":"Huang","year":"2010","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5654","DOI":"10.1016\/j.ejmech.2011.09.043","article-title":"Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the p53-MDM2 protein-protein interaction","volume":"46","author":"Zhuang","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ejmech.2012.08.003","article-title":"Structure-activity relationship and antitumor activity of thio-benzodiazepines as p53-MDM2 protein-protein interaction inhibitors","volume":"56","author":"Guo","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"15741","DOI":"10.3390\/ijms150915741","article-title":"Design, synthesis and biological evaluation of sulfamide and triazole benzodiazepines as novel p53-MDM2 inhibitors","volume":"15","author":"Yu","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1016\/j.bmcl.2004.12.061","article-title":"Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction","volume":"15","author":"Hardcastle","year":"2005","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"6209","DOI":"10.1021\/jm0601194","article-title":"Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold","volume":"49","author":"Hardcastle","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"16038","DOI":"10.1021\/ja8062088","article-title":"Analysis of chemical shift changes reveals the binding modes of isoindolinone inhibitors of the MDM2-p53 interaction","volume":"130","author":"Riedinger","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1021\/jm1011929","article-title":"Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein-protein interaction: Structure-activity studies leading to improved potency","volume":"54","author":"Hardcastle","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1747-0285.2011.01091.x","article-title":"Understanding small-molecule binding to MDM2: Insights into structural effects of isoindolinone inhibitors from NMR spectroscopy","volume":"77","author":"Riedinger","year":"2011","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_86","first-page":"5916","article-title":"MDM2-p53 protein-protein interaction inhibitors: A-ring substituted isoindolinones","volume":"21","author":"Watson","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.ejps.2014.10.006","article-title":"Oxazoloisoindolinones with in vitro antitumor activity selectively activate a p53-pathway through potential inhibition of the p53-MDM2 interaction","volume":"66","author":"Soares","year":"2015","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"7044","DOI":"10.1021\/jm900681h","article-title":"Discovery and optimization of chromenotriazolopyrimidines as potent inhibitors of the mouse double minute 2-tumor protein 53 protein-protein interaction","volume":"52","author":"Allen","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2752","DOI":"10.1016\/j.bmcl.2010.11.027","article-title":"Improvement of the synthesis and pharmacokinetic properties of chromenotriazolopyrimidine MDM2-p53 protein-protein inhibitors","volume":"21","author":"Beck","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"10130","DOI":"10.1021\/ja051147z","article-title":"Structure-based design of potent non-peptide MDM2 inhibitors","volume":"127","author":"Ding","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3432","DOI":"10.1021\/jm051122a","article-title":"Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction","volume":"49","author":"Ding","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"5949","DOI":"10.1016\/j.tetlet.2005.06.114","article-title":"Synthesis of spirooxindoles via asymmetric 1,3-dipolar cycloaddition","volume":"46","author":"Ding","year":"2005","journal-title":"Tetrahedron Lett."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"7970","DOI":"10.1021\/jm901400z","article-title":"Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction","volume":"52","author":"Yu","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3933","DOI":"10.1073\/pnas.0708917105","article-title":"Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition","volume":"105","author":"Shangary","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"5553","DOI":"10.1021\/jm4005708","article-title":"A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice","volume":"56","author":"Zhao","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5855","DOI":"10.1158\/0008-5472.CAN-14-0799","article-title":"SAR405838: An optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression","volume":"74","author":"Wang","year":"2014","journal-title":"Cancer Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"7223","DOI":"10.1021\/ja3125417","article-title":"Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors","volume":"135","author":"Zhao","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"10486","DOI":"10.1021\/jm501541j","article-title":"Design of chemically stable, potent, and efficacious MDM2 inhibitors that exploit the retro-mannich ring-opening-cyclization reaction mechanism in spiro-oxindoles","volume":"57","author":"Aguilar","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"4001","DOI":"10.1016\/j.bmc.2014.05.072","article-title":"Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy","volume":"22","author":"Zhang","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1021\/op3003213","article-title":"Synthesis of a spiroindolinone pyrrolidinecarboxamide MDM2 antagonist","volume":"17","author":"Shu","year":"2013","journal-title":"Org. Process Res. Dev."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1021\/ml400359z","article-title":"Discovery of potent and orally active p53-MDM2 inhibitors RO5353 and RO2468 for potential clinical development","volume":"5","author":"Zhang","year":"2014","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"8319","DOI":"10.1021\/jm100838z","article-title":"Identification of the spiro(oxindole-3,3\u2032-thiazolidine)-based derivatives as potential p53 activity modulators","volume":"53","author":"Bertamino","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Costa, B., Bendinelli, S., Gabelloni, P., Da Pozzo, E., Daniele, S., Scatena, F., Vanacore, R., Campiglia, P., Bertamino, A., and Gomez-Monterrey, I. (2013). Human glioblastoma multiforme: p53 reactivation by a novel MDM2 inhibitor. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072281"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"5407","DOI":"10.1021\/jm400311n","article-title":"Synthesis, in vitro, and in cell studies of a new series of indoline-3,2\u2032-thiazolidine-based p53 modulators","volume":"56","author":"Bertamino","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/bjc.2014.577","article-title":"New small molecules, ISA27 and SM13, inhibit tumour growth inducing mitochondrial effects of p53","volume":"112","author":"Sorriento","year":"2015","journal-title":"Br. J. Cancer"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.bmc.2014.12.037","article-title":"Design and synthesis of new bioisosteres of spirooxindoles (MI-63\/219) as anti-breast cancer agents","volume":"23","author":"Kumar","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.bmcl.2014.09.070","article-title":"Design, synthesis and biological evaluation of novel potent MDM2\/p53 small-molecule inhibitors","volume":"25","author":"Ivanenkov","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.tetlet.2011.10.139","article-title":"Efficient synthesis of spiroisoxazoline oxindoles","volume":"53","author":"Ribeiro","year":"2012","journal-title":"Tetrahedron Lett."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.bmc.2013.10.048","article-title":"Synthesis and evaluation of spiroisoxazoline oxindoles as anticancer agents","volume":"22","author":"Ribeiro","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1039\/C5MD00450K","article-title":"Spirooxadiazoline oxindoles with promising in vitro antitumor activities","volume":"7","author":"Ribeiro","year":"2016","journal-title":"Med. Chem. Comm."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.ejmech.2014.04.023","article-title":"Synthesis of novel spiropyrazoline oxindoles and evaluation of cytotoxicity in cancer cell lines","volume":"79","author":"Monteiro","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"9735","DOI":"10.1016\/j.tet.2014.08.005","article-title":"Recent advances in the synthesis of biologically active spirooxindoles","volume":"70","author":"Santos","year":"2014","journal-title":"Tetrahedron"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"5352","DOI":"10.1002\/anie.201001343","article-title":"Robust generation of lead compounds for protein-protein interactions by computational and mcr chemistry: P53\/HDM2 antagonists","volume":"49","author":"Czarna","year":"2010","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.4161\/cc.9.6.10956","article-title":"Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX\/MDM2 antagonist drug discovery","volume":"9","author":"Popowicz","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1002\/cmdc.201100428","article-title":"Exhaustive fluorine scanning toward potent p53-MDM2 antagonists","volume":"7","author":"Huang","year":"2012","journal-title":"ChemMedChem"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"5979","DOI":"10.1021\/jm400487c","article-title":"Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development","volume":"56","author":"Ding","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"3742","DOI":"10.1158\/1078-0432.CCR-14-0460","article-title":"Preclinical optimization of MDM2 antagonist scheduling for cancer treatment by using a model-based approach","volume":"20","author":"Higgins","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"4053","DOI":"10.1021\/jm400293z","article-title":"Rational design and binding mode duality of MDM2-p53 inhibitors","volume":"56","author":"Sun","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"4936","DOI":"10.1021\/jm300354j","article-title":"Structure-based design of novel inhibitors of the MDM2-p53 interaction","volume":"55","author":"Rew","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"17059","DOI":"10.1021\/ja305839b","article-title":"Ordering of the N-terminus of human MDM2 by small molecule inhibitors","volume":"134","author":"Michelsen","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"6332","DOI":"10.1021\/jm500627s","article-title":"Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer","volume":"57","author":"Rew","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"12855","DOI":"10.1021\/ja305123v","article-title":"An expeditious synthesis of the MDM2-p53 inhibitor AM-8553","volume":"134","author":"Lucas","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"4934","DOI":"10.1021\/jm3007068","article-title":"AM-8553: A novel MDM2 inhibitor with a promising outlook for potential clinical development","volume":"55","author":"Bernard","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1021\/jm401753e","article-title":"Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development","volume":"57","author":"Sun","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"3782","DOI":"10.1016\/j.bmcl.2014.06.073","article-title":"Optimization beyond AMG 232: Discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein-protein interaction","volume":"24","author":"Wang","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1021\/ml500142b","article-title":"Discovery of potent and simplified piperidinone-based inhibitors of the MDM2-p53 interaction","volume":"5","author":"Yu","year":"2014","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1158\/1535-7163.MCT-14-0710","article-title":"The MDM2 inhibitor AMG 232 demonstrates robust antitumor efficacy and potentiates the activity of p53-inducing cytotoxic agents","volume":"14","author":"Canon","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2963","DOI":"10.1021\/jm401911v","article-title":"Novel inhibitors of the MDM2-p53 interaction featuring hydrogen bond acceptors as carboxylic acid isosteres","volume":"57","author":"Gonzalez","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"10499","DOI":"10.1021\/jm501550p","article-title":"Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction","volume":"57","author":"Rew","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1021\/jm401767k","article-title":"Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction","volume":"57","author":"Gonzalez","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"3621","DOI":"10.1016\/j.bmcl.2015.06.058","article-title":"Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode","volume":"17","author":"Gessier","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1158\/1535-7163.MCT-04-0342","article-title":"P53 alpha-helix mimetics antagonize p53\/MDM2 interaction and activate p53","volume":"4","author":"Chen","year":"2005","journal-title":"Mol. Cancer Ther."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"2704","DOI":"10.1002\/anie.200462316","article-title":"Terphenyl-based helical mimetics that disrupt the p53\/HDM2 interaction","volume":"44","author":"Yin","year":"2005","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"9630","DOI":"10.1021\/jm300969t","article-title":"Discovery, synthesis, and biological evaluation of orally active pyrrolidone derivatives as novel inhibitors of p53-MDM2 protein-protein interaction","volume":"55","author":"Zhuang","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1016\/j.bmcl.2014.04.063","article-title":"Discovery of 1-arylpyrrolidone derivatives as potent p53-MDM2 inhibitors based on molecule fusing strategy","volume":"24","author":"Li","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1021\/jm401800k","article-title":"Double-edged swords as cancer therapeutics: Novel, orally active, small molecules simultaneously inhibit p53-MDM2 interaction and the NF-kappaB pathway","volume":"57","author":"Zhuang","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"10830","DOI":"10.18632\/oncotarget.2521","article-title":"A novel drug discovery strategy: Mechanistic investigation of an enantiomeric antitumor agent targeting dual p53 and NF-\u03baB pathways","volume":"5","author":"Zhuang","year":"2014","journal-title":"Oncotarget"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/j.bmcl.2014.01.026","article-title":"Substituted piperidines as HDM2 inhibitors","volume":"24","author":"Ma","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1016\/j.bmcl.2014.02.055","article-title":"Core modification of substituted piperidines as novel inhibitors of HDM2-p53 protein-protein interaction","volume":"24","author":"Pan","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1021\/ml500019s","article-title":"Pivotal role of an aliphatic side chain in the development of an HDM2 inhibitor","volume":"5","author":"Ma","year":"2014","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.ejmech.2014.05.027","article-title":"Design, synthesis and in vitro and in vivo antitumour activity of 3-benzylideneindolin-2-one derivatives, a novel class of small-molecule inhibitors of the MDM2-p53 interaction","volume":"81","author":"Zheng","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"3759","DOI":"10.1021\/jm060023+","article-title":"Discovery of a nanomolar inhibitor of the human murine double minute 2 (MDM2)-p53 interaction through an integrated, virtual database screening strategy","volume":"49","author":"Lu","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"12809","DOI":"10.1021\/ja073687x","article-title":"Small molecule inhibitors of the MDM2-p53 interaction discovered by ensemble-based receptor models","volume":"129","author":"Bowman","year":"2007","journal-title":"J. Am. Chem. Soc."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1016\/j.bmcl.2014.03.039","article-title":"Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction","volume":"24","author":"Vaupel","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"5349","DOI":"10.1002\/j.1460-2075.1996.tb00919.x","article-title":"MDMX: A novel p53-binding protein with some functional properties of MDM2","volume":"15","author":"Shvarts","year":"1996","journal-title":"EMBO J."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.bbrc.2005.03.151","article-title":"MDMX as an essential regulator of p53 activity","volume":"331","author":"Marine","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nrc3430","article-title":"MDM2, MDMX and p53 in oncogenesis and cancer therapy","volume":"13","author":"Wade","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1101\/gad.16722111","article-title":"Validation of MDMX as a therapeutic target for reactivating p53 in tumors","volume":"25","author":"Garcia","year":"2011","journal-title":"Genes Dev."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"10786","DOI":"10.1074\/jbc.M109.056747","article-title":"Identification and characterization of the first small molecule inhibitor of MDMX","volume":"285","author":"Reed","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Bista, M., Smithson, D., Pecak, A., Salinas, G., Pustelny, K., Min, J., Pirog, A., Finch, K., Zdzalik, M., and Waddell, B. (2012). On the mechanism of action of SJ-172550 in inhibiting the interaction of MDM4 and p53. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037518"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1002\/ijc.20968","article-title":"Pilot screening programme for small molecule activators of p53","volume":"115","author":"Berkson","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1593\/neo.11438","article-title":"A small-molecule p53 activator induces apoptosis through inhibiting MDMX expression in breast cancer cells","volume":"13","author":"Wang","year":"2011","journal-title":"Neoplasia"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1007\/s10495-014-1026-8","article-title":"XI-011 enhances cisplatin-induced apoptosis by functional restoration of p53 in head and neck cancer","volume":"19","author":"Roh","year":"2014","journal-title":"Apoptosis"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"11788","DOI":"10.1073\/pnas.1203789109","article-title":"Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization","volume":"109","author":"Graves","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.phrs.2015.03.006","article-title":"A tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins","volume":"95\u201396","author":"Soares","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1039\/c3md00161j","article-title":"Diaryl- and triaryl-pyrrole derivatives: Inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactions","volume":"4","author":"Blackburn","year":"2013","journal-title":"Med. Chem. Commun."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"5661","DOI":"10.1016\/j.bmcl.2015.11.019","article-title":"2,3\u2032-bis(1\u2032H-indole) heterocycles: New p53\/MDM2\/MDMX antagonists","volume":"25","author":"Neochoritis","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ccr.2014.01.021","article-title":"Mutant p53 in cancer: New functions and therapeutic opportunities","volume":"25","author":"Muller","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"2622","DOI":"10.1016\/j.febslet.2014.04.017","article-title":"Mutant p53 reactivation by small molecules makes its way to the clinic","volume":"588","author":"Bykov","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.canlet.2015.01.014","article-title":"Acute cytotoxicity of MIRA-1\/NSC19630, a mutant p53-reactivating small molecule, against human normal and cancer cells via a caspase-9-dependent apoptosis","volume":"359","author":"Jarry","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1038\/nm1146","article-title":"Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors","volume":"10","author":"Issaeva","year":"2004","journal-title":"Nat. Med."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1038\/nm1105-1135","article-title":"NMR indicates that the small molecule RITA does not block p53-MDM2 binding in vitro","volume":"11","author":"Krajewski","year":"2005","journal-title":"Nat. Med."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.4161\/cc.9.9.11545","article-title":"Rescue of the apoptotic-inducing function of mutant p53 by small molecule RITA","volume":"9","author":"Zhao","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"5092","DOI":"10.1158\/1078-0432.CCR-12-2211","article-title":"Dual targeting of wild-type and mutant p53 by small molecule RITA results in the inhibition of N-Myc and key survival oncogenes and kills neuroblastoma cells in vivo and in vitro","volume":"19","author":"Burmakin","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1038\/cdd.2011.45","article-title":"Abrogation of Wip1 expression by RITA-activated p53 potentiates apoptosis induction via activation of ATM and inhibition of HDMX","volume":"18","author":"Spinnler","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"9734","DOI":"10.1039\/c2ob26627j","article-title":"Efficient synthesis of RITA and its analogues: Derivation of analogues with improved antiproliferative activity via modulation of p53\/MIR-34a pathway","volume":"10","author":"Lin","year":"2012","journal-title":"Org. Biomol. Chem."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"6635","DOI":"10.1016\/j.tetlet.2014.10.074","article-title":"Synthesis and antiproliferative activity of RITA and its analogs","volume":"55","author":"Jiang","year":"2014","journal-title":"Tetrahedron Lett."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"10360","DOI":"10.1073\/pnas.0805326105","article-title":"Targeted rescue of a destabilized mutant of p53 by an in silico screened drug","volume":"105","author":"Boeckler","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"6810","DOI":"10.1021\/ja301056a","article-title":"Halogen-enriched fragment libraries as leads for drug rescue of mutant p53","volume":"134","author":"Wilcken","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"6034","DOI":"10.1093\/nar\/gkt305","article-title":"Small molecule induced reactivation of mutant p53 in cancer cells","volume":"41","author":"Liu","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/nm0302-282","article-title":"Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound","volume":"8","author":"Bykov","year":"2002","journal-title":"Nat. Med."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.ccr.2009.03.003","article-title":"PRIMA-1 reactivates mutant p53 by covalent binding to the core domain","volume":"15","author":"Lambert","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1016\/j.canlet.2014.10.034","article-title":"SAHA triggered MET activation contributes to SAHA tolerance in solid cancer cells","volume":"356","author":"Ding","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1038\/ncomms2361","article-title":"Computational identification of a transiently open L1\/S3 pocket for reactivation of mutant p53","volume":"4","author":"Wassman","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"47","DOI":"10.4161\/cbt.1.1.41","article-title":"The mutant p53-conformation modifying drug, CP-31398, can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein","volume":"1","author":"Takimoto","year":"2002","journal-title":"Cancer Biol. Ther."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1128\/MCB.23.6.2171-2181.2003","article-title":"Stabilization of p53 by CP-31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 20 or MDM2 binding","volume":"23","author":"Wang","year":"2003","journal-title":"Mol. Cell Biol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.molonc.2008.02.004","article-title":"Mutant p53 targeting by the low molecular weight compound STIMA-1","volume":"2","author":"Zache","year":"2008","journal-title":"Mol. Oncol."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"30384","DOI":"10.1074\/jbc.M501664200","article-title":"Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs","volume":"280","author":"Bykov","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"10198","DOI":"10.1074\/jbc.M109.083469","article-title":"SCH529074, a small molecule activator of mutant p53, which binds p53 DNA binding domain (DBD), restores growth-suppressive function to mutant p53 and interrupts HDM2-mediated ubiquitination of wild type p53","volume":"285","author":"Demma","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.ccr.2012.03.042","article-title":"Allele-specific p53 mutant reactivation","volume":"21","author":"Yu","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"8879","DOI":"10.18632\/oncotarget.2432","article-title":"Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc-metallochaperone based mechanism","volume":"5","author":"Yu","year":"2014","journal-title":"Oncotarget"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1016\/j.chembiol.2015.07.016","article-title":"Small-molecule reactivation of mutant p53 to wild-type-like p53 through the p53-HSP40 regulatory axis","volume":"22","author":"Hiraki","year":"2015","journal-title":"Chem. Biol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"4326","DOI":"10.18632\/oncotarget.6775","article-title":"Reactivation of wild-type and mutant p53 by tryptophanol-derived oxazoloisoindolinone SLMP53-1, a novel anticancer small-molecule","volume":"7","author":"Soares","year":"2016","journal-title":"Oncotarget"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1038\/cdd.2011.71","article-title":"Saha shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-HSP90 chaperone axis","volume":"18","author":"Li","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"6302","DOI":"10.1073\/pnas.0802091105","article-title":"Small-molecule retra suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway","volume":"105","author":"Kravchenko","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.4161\/cbt.7.12.7461","article-title":"Non-genotoxic anti-neoplastic effects of ellipticine derivative NSC176327 in p53-deficient human colon carcinoma cells involve stimulation of p73","volume":"7","author":"Lu","year":"2008","journal-title":"Cancer Biol. Ther."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"2954","DOI":"10.1038\/bjc.2013.702","article-title":"P53-based cyclotherapy: Exploiting the \u201cguardian of the genome\u201d to protect normal cells from cytotoxic therapy","volume":"109","author":"Rao","year":"2013","journal-title":"Br. J. Cancer"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/9\/2\/25\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:23:51Z","timestamp":1760210631000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/9\/2\/25"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5,13]]},"references-count":187,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2016,6]]}},"alternative-id":["ph9020025"],"URL":"https:\/\/doi.org\/10.3390\/ph9020025","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2016,5,13]]}}}