{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T18:33:45Z","timestamp":1778610825597,"version":"3.51.4"},"reference-count":87,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T00:00:00Z","timestamp":1663718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Coimbra"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Proteolysis-targeting chimeras (PROTACs) are molecules that selectively degrade a protein of interest (POI). The incorporation of ligands that recruit mouse double minute 2 (MDM2) into PROTACs, forming the so-called MDM2-based PROTACs, has shown promise in cancer treatment due to its dual mechanism of action: a PROTAC that recruits MDM2 prevents its binding to p53, resulting not only in the degradation of POI but also in the increase of intracellular levels of the p53 suppressor, with the activation of a whole set of biological processes, such as cell cycle arrest or apoptosis. In addition, these PROTACs, in certain cases, allow for the degradation of the target, with nanomolar potency, in a rapid and sustained manner over time, with less susceptibility to the development of resistance and tolerance, without causing changes in protein expression, and with selectivity to the target, including the respective isoforms or mutations, and to the cell type, overcoming some limitations associated with the use of inhibitors for the same therapeutic target. Therefore, the aim of this review is to analyze and discuss the characteristics of MDM2-based PROTACs developed for the degradation of oncogenic proteins and to understand what potential they have as future anticancer drugs.<\/jats:p>","DOI":"10.3390\/ijms231911068","type":"journal-article","created":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T01:47:06Z","timestamp":1663811226000},"page":"11068","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["MDM2-Based Proteolysis-Targeting Chimeras (PROTACs): An Innovative Drug Strategy for Cancer Treatment"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7193-4025","authenticated-orcid":false,"given":"Andr\u00e9 T. S.","family":"Vicente","sequence":"first","affiliation":[{"name":"Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0779-6083","authenticated-orcid":false,"given":"Jorge A. R.","family":"Salvador","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,21]]},"reference":[{"key":"ref_1","unstructured":"National Cancer Institute (2022, July 01). What is Cancer?, Available online: https:\/\/www.cancer.gov\/about-cancer\/understanding\/what-is-cancer."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"a028332","DOI":"10.1101\/cshperspect.a028332","article-title":"Homeostasis Back and Forth: An Ecoevolutionary Perspective of Cancer","volume":"7","author":"Basanta","year":"2017","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","unstructured":"World Health Organisation (WHO) Media Centre (2022, July 01). Cancer\u2014Key Facts. Available online: http:\/\/www.who.int\/news-room\/fact-sheets\/detail\/cancer."},{"key":"ref_5","unstructured":"(2022, July 01). Cancer Research UK\u2014What is Cancer?. Available online: https:\/\/www.cancerresearchuk.org\/about-cancer\/what-is-cancer."},{"key":"ref_6","unstructured":"World Health Organisation (WHO) (2022, July 01). Cancer. Available online: https:\/\/www.who.int\/health-topics\/cancer."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1007\/s00044-020-02574-9","article-title":"Anticancer strategies by upregulating p53 through inhibition of its ubiquitination by MDM2","volume":"29","author":"Anifowose","year":"2020","journal-title":"Med. Chem. Res."},{"key":"ref_8","first-page":"5762","article-title":"Therapeutic opportunities in cancer therapy: Targeting the p53-MDM2\/MDMX interactions","volume":"11","author":"Munisamy","year":"2021","journal-title":"Am. J. Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/s41568-021-00365-x","article-title":"Advancing targeted protein degradation for cancer therapy","volume":"21","author":"Dale","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5214","DOI":"10.1039\/D2CS00193D","article-title":"PROTACs: Past, present and future","volume":"51","author":"Li","year":"2022","journal-title":"Chem. Soc. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7066","DOI":"10.1039\/D2CS00220E","article-title":"Chemistries of bifunctional PROTAC degraders","volume":"51","author":"Cao","year":"2022","journal-title":"Chem. Soc. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.semcancer.2020.02.006","article-title":"PROTACs: A novel strategy for cancer therapy","volume":"67","author":"Liu","year":"2020","journal-title":"Semin. Cancer Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrd.2016.211","article-title":"Induced protein degradation: An emerging drug discovery paradigm","volume":"16","author":"Lai","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"915","DOI":"10.4155\/fmc-2019-0340","article-title":"Small-molecule PROTACs: Novel agents for cancer therapy","volume":"12","author":"Wan","year":"2020","journal-title":"Futur. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41573-021-00371-6","article-title":"PROTAC targeted protein degraders: The past is prologue","volume":"21","author":"Langley","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ddtec.2019.01.002","article-title":"PROteolysis TArgeting Chimeras (PROTACs)\u2014Past, present and future","volume":"31","author":"Pettersson","year":"2019","journal-title":"Drug Discov. Today Technol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8554","DOI":"10.1073\/pnas.141230798","article-title":"Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation","volume":"98","author":"Sakamoto","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/cbf.3369","article-title":"The PROTAC technology in drug development","volume":"37","author":"Zou","year":"2019","journal-title":"Cell Biochem. Funct."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1080\/17460441.2019.1659242","article-title":"PROTACs\u2013 a game-changing technology","volume":"14","author":"Konstantinidou","year":"2019","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5904","DOI":"10.1016\/j.bmcl.2008.07.114","article-title":"Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics","volume":"18","author":"Schneekloth","year":"2008","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.tcb.2013.12.003","article-title":"Perilous journey: A tour of the ubiquitin\u2013proteasome system","volume":"24","author":"Kleiger","year":"2014","journal-title":"Trends Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/458421a","article-title":"The ubiquitin system","volume":"458","author":"Nath","year":"2009","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.biocel.2018.06.001","article-title":"Ubiquitination: Friend and foe in cancer","volume":"101","author":"Mansour","year":"2018","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e202100270","DOI":"10.1002\/cbic.202100270","article-title":"Recent Developments in PROTAC-Mediated Protein Degradation: From Bench to Clinic","volume":"23","author":"Hu","year":"2022","journal-title":"ChemBioChem"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"116221","DOI":"10.1016\/j.bmc.2021.116221","article-title":"In vivo synthetic chemistry of proteolysis targeting chimeras (PROTACs)","volume":"41","author":"Tomoshige","year":"2021","journal-title":"Bioorganic Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1038\/nrd2056","article-title":"Drug discovery in the ubiquitin\u2013proteasome system","volume":"5","author":"Nalepa","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"112539","DOI":"10.1016\/j.ejmech.2020.112539","article-title":"PROTAC: A promising technology for cancer treatment","volume":"203","author":"Zhou","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1074\/mcp.T300009-MCP200","article-title":"Development of Protacs to Target Cancer-promoting Proteins for Ubiquitination and Degradation","volume":"2","author":"Sakamoto","year":"2003","journal-title":"Mol. Cell. Proteom."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3748","DOI":"10.1021\/ja039025z","article-title":"Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation","volume":"126","author":"Schneekloth","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7201","DOI":"10.1038\/onc.2008.320","article-title":"Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer","volume":"27","author":"Cyrus","year":"2008","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5820","DOI":"10.1021\/ja100691p","article-title":"Protein Knockdown Using Methyl Bestatin\u2212Ligand Hybrid Molecules: Design and Synthesis of Inducers of Ubiquitination-Mediated Degradation of Cellular Retinoic Acid-Binding Proteins","volume":"132","author":"Itoh","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/j.febslet.2011.03.019","article-title":"Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein","volume":"585","author":"Okuhira","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1124\/mol.116.105569","article-title":"Targeted Degradation of Proteins Localized in Subcellular Compartments by Hybrid Small Molecules","volume":"91","author":"Okuhira","year":"2016","journal-title":"Mol. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4556","DOI":"10.1074\/jbc.M116.768853","article-title":"In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs)","volume":"292","author":"Ohoka","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"11463","DOI":"10.1002\/anie.201206231","article-title":"Small-Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1\u03b1","volume":"51","author":"Buckley","year":"2012","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1126\/science.aab1433","article-title":"Phthalimide conjugation as a strategy for in vivo target protein degradation","volume":"348","author":"Winter","year":"2015","journal-title":"Science"},{"key":"ref_37","unstructured":"ARVINAS\u00ae (2022, June 03). Androgen Receptor. Available online: https:\/\/www.arvinas.com\/pipeline-programs\/androgen-receptor."},{"key":"ref_38","unstructured":"ARVINAS\u00ae (2022, June 03). Estrogen Receptor. Available online: https:\/\/www.arvinas.com\/pipeline-programs\/estrogen-receptor."},{"key":"ref_39","unstructured":"ARVINAS\u00ae (2022, June 03). Pipeline Programs. Available online: https:\/\/www.arvinas.com\/pipeline-programs\/pipeline."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8942","DOI":"10.1073\/pnas.1217206110","article-title":"Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs","volume":"110","author":"Hines","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"eaay5154","DOI":"10.1126\/sciadv.aay5154","article-title":"Light-induced control of protein destruction by opto-PROTAC","volume":"6","author":"Liu","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"eaay5064","DOI":"10.1126\/sciadv.aay5064","article-title":"PHOTACs enable optical control of protein degradation","volume":"6","author":"Reynders","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1021\/acscentsci.9b00713","article-title":"Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs","volume":"5","author":"Pfaff","year":"2019","journal-title":"ACS Cent. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1021\/acscentsci.6b00280","article-title":"Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras","volume":"2","author":"Lebraud","year":"2016","journal-title":"ACS Central Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1021\/acschembio.0c00285","article-title":"Antibody\u2013PROTAC Conjugates Enable HER2-Dependent Targeted Protein Degradation of BRD","volume":"15","author":"Maneiro","year":"2020","journal-title":"ACS Chem. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6768","DOI":"10.1016\/j.bmc.2011.09.041","article-title":"Design, synthesis and biological evaluation of nuclear receptor-degradation inducers","volume":"19","author":"Itoh","year":"2011","journal-title":"Bioorganic Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.chembiol.2019.11.014","article-title":"Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling","volume":"27","author":"You","year":"2019","journal-title":"Cell Chem. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1021\/acsmedchemlett.7b00247","article-title":"Targeting the Allosteric Site of Oncoprotein BCR-ABL as an Alternative Strategy for Effective Target Protein Degradation","volume":"8","author":"Shimokawa","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1021\/acschembio.8b01094","article-title":"PROTAC-Mediated Degradation of Bruton\u2019s Tyrosine Kinase Is Inhibited by Covalent Binding","volume":"14","author":"Tinworth","year":"2019","journal-title":"ACS Chem. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3474","DOI":"10.1039\/D0SC00167H","article-title":"Systematic exploration of different E3 ubiquitin ligases: An approach towards potent and selective CDK6 degraders","volume":"11","author":"Steinebach","year":"2020","journal-title":"Chem. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/j.chembiol.2017.05.024","article-title":"Targeted Protein Degradation: From Chemical Biology to Drug Discovery","volume":"24","author":"Cromm","year":"2017","journal-title":"Cell Chem. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Ryu, M.Y., Cho, S.K., Hong, Y., Kim, J., Kim, J.H., Kim, G.M., Chen, Y.-J., Knoch, E., M\u00f8ller, B.L., and Kim, W.T. (2019). Classification of barley U-box E3 ligases and their expression patterns in response to drought and pathogen stresses. BMC Genom., 20.","DOI":"10.1186\/s12864-019-5696-z"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s43556-021-00043-2","article-title":"E3 ubiquitin ligases: Styles, structures and functions","volume":"2","author":"Yang","year":"2021","journal-title":"Mol. Biomed."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1146\/annurev-biochem-060815-014922","article-title":"Ubiquitin Ligases: Structure, Function, and Regulation","volume":"86","author":"Zheng","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1016\/j.bmcl.2019.04.030","article-title":"Proteolysis targeting chimeras (PROTACs) in \u2018beyond rule-of-five\u2019 chemical space: Recent progress and future challenges","volume":"29","author":"Edmondson","year":"2019","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"a026104","DOI":"10.1101\/cshperspect.a026104","article-title":"The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression","volume":"6","author":"Chen","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_57","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_58","doi-asserted-by":"crossref","unstructured":"Koo, N., Sharma, A.K., and Narayan, S. (2022). Therapeutics Targeting p53-MDM2 Interaction to Induce Cancer Cell Death. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095005"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1073\/pnas.76.5.2420","article-title":"Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse","volume":"76","author":"DeLeo","year":"1979","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/s000180050273","article-title":"Functions of the MDM2 oncoprotein","volume":"55","author":"Freedman","year":"1999","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1146\/annurev-pathol-012414-040349","article-title":"The Roles of MDM2 and MDMX in Cancer","volume":"11","author":"Lokshin","year":"2016","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"15608","DOI":"10.1073\/pnas.95.26.15608","article-title":"Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis","volume":"95","author":"Jones","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","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_64","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s12943-022-01535-7","article-title":"Clinical considerations for the design of PROTACs in cancer","volume":"21","author":"Morafraile","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1016\/j.apsb.2020.11.022","article-title":"Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer","volume":"11","author":"He","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/s41422-018-0055-1","article-title":"PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies","volume":"28","author":"Sun","year":"2018","journal-title":"Cell Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1158\/0008-5472.CAN-18-2918","article-title":"MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53","volume":"79","author":"Hines","year":"2019","journal-title":"Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1039\/C8CC07813K","article-title":"Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule","volume":"55","author":"Zhao","year":"2019","journal-title":"Chem. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4313","DOI":"10.1021\/acs.molpharmaceut.9b00673","article-title":"TrkC-Targeted Kinase Inhibitors and PROTACs","volume":"16","author":"Zhao","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1021\/acsmedchemlett.9b00025","article-title":"Identification of New Small-Molecule Inducers of Estrogen-related Receptor \u03b1 (ERR\u03b1) Degradation","volume":"10","author":"Peng","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"7575","DOI":"10.1021\/acs.jmedchem.9b00871","article-title":"Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders","volume":"62","author":"Su","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"114013","DOI":"10.1016\/j.ejmech.2021.114013","article-title":"Discovery of BP3 as an efficacious proteolysis targeting chimera (PROTAC) degrader of HSP90 for treating breast cancer","volume":"228","author":"Liu","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"112199","DOI":"10.1016\/j.ejmech.2020.112199","article-title":"Design and synthesis of selective degraders of EGFRL858R\/T790M mutant","volume":"192","author":"Zhang","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biomaterials.2019.03.004","article-title":"A tetrameric protein scaffold as a nano-carrier of antitumor peptides for cancer therapy","volume":"204","author":"Ma","year":"2019","journal-title":"Biomaterials"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2104850","DOI":"10.1002\/advs.202104850","article-title":"Kill Two Birds with One Stone: A Multifunctional Dual-Targeting Protein Drug to Overcome Imatinib Resistance in Philadelphia Chromosome-Positive Leukemia","volume":"9","author":"Ma","year":"2022","journal-title":"Adv. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2021.06.006","article-title":"Androgen receptor (AR) heterogeneity in prostate cancer and therapy resistance","volume":"518","author":"Jamroze","year":"2021","journal-title":"Cancer Lett."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12943-018-0779-z","article-title":"Role of Bruton\u2019s tyrosine kinase in B cells and malignancies","volume":"17","author":"Singh","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1038\/s41419-020-03015-6","article-title":"The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells","volume":"11","author":"Qin","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2100180","DOI":"10.1002\/bies.202100180","article-title":"BRD4 in physiology and pathology: \u2018\u2018BET\u2019\u2019 on its partners","volume":"43","author":"Liang","year":"2021","journal-title":"BioEssays News Rev. Mol. Cell. Dev. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1177\/2040620715576662","article-title":"Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: Emerging preclinical and clinical evidence","volume":"6","author":"Chaidos","year":"2015","journal-title":"Ther. Adv. Hematol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"5979","DOI":"10.1021\/jm400487c","article-title":"Discovery of RG7388, a Potent and Selective p53\u2013MDM2 Inhibitor in Clinical Development","volume":"56","author":"Ding","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_82","unstructured":"U.S. National Library of Medicine (2022, June 17). Search of: RG7388 OR RO-5503781\u2014List Results\u2014ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/ct2\/results?intr=RG7388+OR+RO5503781&Search=Apply&age_v=&gndr=&type=&rslt=."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"807","DOI":"10.2217\/fon-2020-0044","article-title":"MIRROS: A randomized, placebo-controlled, Phase III trial of cytarabine \u00b1 idasanutlin in relapsed or refractory acute myeloid leukemia","volume":"16","author":"Montesinos","year":"2020","journal-title":"Futur. Oncol."},{"key":"ref_84","unstructured":"World Health Organization (2022, June 18). Colorectal Cancer Awareness Month 2022\u2014IARC. Available online: https:\/\/www.iarc.who.int\/featured-news\/colorectal-cancer-awareness-month-2022\/."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"103125","DOI":"10.1016\/j.dnarep.2021.103125","article-title":"PARP1: Structural insights and pharmacological targets for inhibition","volume":"103","author":"Spiegel","year":"2021","journal-title":"DNA Repair"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s12943-021-01434-3","article-title":"Proteolysis-targeting chimeras (PROTACs) in cancer therapy","volume":"21","author":"Li","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.ebiom.2018.09.005","article-title":"Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs","volume":"36","author":"An","year":"2018","journal-title":"eBioMedicine"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11068\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:36:25Z","timestamp":1760142985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11068"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,21]]},"references-count":87,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms231911068"],"URL":"https:\/\/doi.org\/10.3390\/ijms231911068","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,21]]}}}