{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:49:14Z","timestamp":1785332954414,"version":"3.55.0"},"reference-count":88,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T00:00:00Z","timestamp":1718064000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T00:00:00Z","timestamp":1718064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["270650915\/GRK 2158"],"award-info":[{"award-number":["270650915\/GRK 2158"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["417677437\/GRK 2578"],"award-info":[{"award-number":["417677437\/GRK 2578"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["270650915\/GRK 2158"],"award-info":[{"award-number":["270650915\/GRK 2158"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["270650915\/GRK 2158"],"award-info":[{"award-number":["270650915\/GRK 2158"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["417677437\/GRK 2578"],"award-info":[{"award-number":["417677437\/GRK 2578"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["270650915\/GRK 2158"],"award-info":[{"award-number":["270650915\/GRK 2158"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["417677437\/GRK 2578"],"award-info":[{"award-number":["417677437\/GRK 2578"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["270650915\/GRK 2158"],"award-info":[{"award-number":["270650915\/GRK 2158"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["270650915\/GRK 2158"],"award-info":[{"award-number":["270650915\/GRK 2158"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Discov."],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A key feature of cancer is the disruption of cell cycle regulation, which is characterized by the selective and abnormal activation of cyclin-dependent kinases (CDKs). Consequently, targeting CDKs via meriolins represents an attractive therapeutic approach for cancer therapy. Meriolins represent a semisynthetic compound class derived from meridianins and variolins with a known CDK inhibitory potential. Here, we analyzed the two novel derivatives meriolin 16 and meriolin 36 in comparison to other potent CDK inhibitors and could show that they displayed a high cytotoxic potential in different lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells. In a kinome screen, we showed that meriolin 16 and 36 prevalently inhibited most of the CDKs (such as CDK1, 2, 3, 5, 7, 8, 9, 12, 13, 16, 17, 18, 19, 20). In drug-to-target modeling studies, we predicted a common binding mode of meriolin 16 and 36 to the ATP-pocket of CDK2 and an additional flipped binding for meriolin 36. We could show that cell cycle progression and proliferation were blocked by abolishing phosphorylation of retinoblastoma protein (a major target of CDK2) at Ser612 and Thr82. Moreover, meriolin 16 prevented the CDK9-mediated phosphorylation of RNA polymerase II at Ser2 which is crucial for transcription initiation. This renders both meriolin derivatives as valuable anticancer drugs as they target three different Achilles\u2019 heels of the tumor: (1) inhibition of cell cycle progression and proliferation, (2) prevention of transcription, and (3) induction of cell death.<\/jats:p>","DOI":"10.1038\/s41420-024-02056-6","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T13:20:36Z","timestamp":1718112036000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Novel meriolin derivatives potently inhibit cell cycle progression and transcription in leukemia and lymphoma cells via inhibition of cyclin-dependent kinases (CDKs)"],"prefix":"10.1038","volume":"10","author":[{"given":"Laura","family":"Schmitt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1485-7453","authenticated-orcid":false,"given":"Julia","family":"Hoppe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Cea-Medina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter-Martin","family":"Bruch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6519-1395","authenticated-orcid":false,"given":"Karina S.","family":"Krings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6124-1885","authenticated-orcid":false,"given":"Ilka","family":"Lechtenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3636-7018","authenticated-orcid":false,"given":"Daniel","family":"Drie\u00dfen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0048-2279","authenticated-orcid":false,"given":"Christoph","family":"Peter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6494-7744","authenticated-orcid":false,"given":"Sanil","family":"Bhatia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sascha","family":"Dietrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4167-7806","authenticated-orcid":false,"given":"Bj\u00f6rn","family":"Stork","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Fritz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Gohlke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9809-724X","authenticated-orcid":false,"given":"Thomas J. J.","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5236-942X","authenticated-orcid":false,"given":"Sebastian","family":"Wesselborg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,11]]},"reference":[{"key":"2056_CR1","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1038\/ncb1109-1275","volume":"11","author":"M Malumbres","year":"2009","unstructured":"Malumbres M, Harlow E, Hunt T, Hunter T, Lahti JM, Manning G, et al. Cyclin-dependent kinases: a family portrait. Nat Cell Biol. 2009;11:1275\u20136.","journal-title":"Nat Cell Biol"},{"key":"2056_CR2","doi-asserted-by":"publisher","first-page":"3079","DOI":"10.1242\/dev.091744","volume":"140","author":"S Lim","year":"2013","unstructured":"Lim S, Kaldis P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development. 2013;140:3079\u201393.","journal-title":"Development."},{"key":"2056_CR3","doi-asserted-by":"publisher","first-page":"244","DOI":"10.2741\/Bregman","volume":"5","author":"DB Bregman","year":"2000","unstructured":"Bregman DB, Pestell RG, Kidd VJ. Cell cycle regulation and RNA polymerase II. Front Biosci. 2000;5:244\u201357.","journal-title":"Front Biosci."},{"key":"2056_CR4","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1002\/jcp.10058","volume":"190","author":"T Oelgeschl\u00e4ger","year":"2002","unstructured":"Oelgeschl\u00e4ger T. Regulation of RNA polymerase II activity by CTD phosphorylation and cell cycle control. J Cell Physiol. 2002;190:160\u20139.","journal-title":"J Cell Physiol"},{"key":"2056_CR5","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41580-021-00404-3","volume":"23","author":"HK Matthews","year":"2021","unstructured":"Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2021;23:74\u201388.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2056_CR6","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1016\/j.tibs.2022.06.007","volume":"47","author":"M Fischer","year":"2022","unstructured":"Fischer M, Schade AE, Branigan TB, M\u00fcller GA, DeCaprio JA. Coordinating gene expression during the cell cycle. Trends Biochem Sci. 2022;47:1009\u201322.","journal-title":"Trends Biochem Sci."},{"key":"2056_CR7","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/s41580-020-0210-7","volume":"21","author":"M Giacomello","year":"2020","unstructured":"Giacomello M, Pyakurel A, Glytsou C, Scorrano L. The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol. 2020;21:204\u201324.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2056_CR8","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1002\/bies.950170603","volume":"17","author":"EA Nigg","year":"1995","unstructured":"Nigg EA. Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle. Bioessays. 1995;17:471\u201380.","journal-title":"Bioessays."},{"key":"2056_CR9","doi-asserted-by":"publisher","first-page":"176","DOI":"10.4103\/1947-2714.157476","volume":"7","author":"AM Abreu Velez","year":"2015","unstructured":"Abreu Velez AM, Howard MS. Tumor-suppressor genes, cell cycle regulatory checkpoints, and the skin. N Am J Med Sci. 2015;7:176\u201388.","journal-title":"N Am J Med Sci"},{"key":"2056_CR10","doi-asserted-by":"publisher","first-page":"2046","DOI":"10.1002\/1873-3468.13867","volume":"594","author":"BR Pennycook","year":"2020","unstructured":"Pennycook BR, Barr AR. Restriction point regulation at the crossroads between quiescence and cell proliferation. FEBS Lett. 2020;594:2046\u201360.","journal-title":"FEBS Lett."},{"key":"2056_CR11","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.molcel.2020.08.020","volume":"80","author":"SM Rubin","year":"2020","unstructured":"Rubin SM, Sage J, Skotheim JM. Integrating old and new paradigms of G1\/S control. Mol Cell. 2020;80:183\u201392.","journal-title":"Mol Cell"},{"key":"2056_CR12","first-page":"1913","volume":"11","author":"M Zhang","year":"2021","unstructured":"Zhang M, Zhang L, Hei R, Li X, Cai H, Wu X, et al. CDK inhibitors in cancer therapy, an overview of recent development. Am J Cancer Res. 2021;11:1913\u201335.","journal-title":"Am J Cancer Res"},{"key":"2056_CR13","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1111\/j.1432-1033.1997.t01-2-00527.x","volume":"243","author":"L Meijer","year":"1997","unstructured":"Meijer L, Borgne A, Mulner O, Chong JP, Blow JJ, Inagaki N, et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin\u2010dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem. 1997;243:527\u201336.","journal-title":"Eur J Biochem"},{"key":"2056_CR14","first-page":"135","volume":"3","author":"J Cicenas","year":"2015","unstructured":"Cicenas J, Kalyan K, Sorokinas A, Stankunas E, Levy J, Meskinyte I, et al. Roscovitine in cancer and other diseases. Ann Transl Med. 2015;3:135\u201346.","journal-title":"Ann Transl Med"},{"key":"2056_CR15","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.pharmthera.2017.02.008","volume":"173","author":"SR Whittaker","year":"2017","unstructured":"Whittaker SR, Mallinger A, Workman P, Clarke PA. Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharm Ther. 2017;173:83\u2013105.","journal-title":"Pharm Ther"},{"key":"2056_CR16","doi-asserted-by":"publisher","first-page":"8325","DOI":"10.1158\/0008-5472.CAN-07-1826","volume":"67","author":"K Bettayeb","year":"2007","unstructured":"Bettayeb K, Tirado OM, Marionneau-Lambot S, Ferandin Y, Lozach O, Morris JC, et al. Meriolins, a new class of cell death inducing kinase inhibitors with enhanced selectivity for cyclin-dependent kinases. Cancer Res. 2007;67:8325\u201334.","journal-title":"Cancer Res."},{"key":"2056_CR17","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1021\/jm700940h","volume":"51","author":"A Echalier","year":"2008","unstructured":"Echalier A, Bettayeb K, Ferandin Y, Lozach O, Clement M, Valette A, et al. Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): Synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2\/cyclin A\/meriolin complex. J Med Chem. 2008;51:737\u201351.","journal-title":"J Med Chem"},{"key":"2056_CR18","doi-asserted-by":"publisher","first-page":"947","DOI":"10.3390\/molecules28030947","volume":"28","author":"M Kruppa","year":"2023","unstructured":"Kruppa M, M\u00fcller TJJ. A survey on the synthesis of variolins, meridianins, and meriolins\u2014naturally occurring marine (aza)indole alkaloids and their semisynthetic derivatives. Molecules. 2023;28:947.","journal-title":"Molecules."},{"key":"2056_CR19","doi-asserted-by":"publisher","first-page":"9470","DOI":"10.1021\/acs.jmedchem.7b00663","volume":"60","author":"U Singh","year":"2017","unstructured":"Singh U, Chashoo G, Khan SU, Mahajan P, Nargotra A, Mahajan G, et al. Design of novel 3-pyrimidinylazaindole CDK2\/9 inhibitors with potent in vitro and in vivo antitumor efficacy in a triple-negative breast cancer model. J Med Chem. 2017;60:9470\u201389.","journal-title":"J Med Chem"},{"key":"2056_CR20","doi-asserted-by":"publisher","first-page":"4420","DOI":"10.1016\/j.bmc.2009.05.017","volume":"17","author":"R Akue-Gedu","year":"2009","unstructured":"Akue-Gedu R, Debiton E, Ferandin Y, Meijer L, Prudhomme M, Anizon F, et al. Synthesis and biological activities of aminopyrimidyl-indoles structurally related to meridianins. Bioorg Med Chem. 2009;17:4420\u20134.","journal-title":"Bioorg Med Chem"},{"key":"2056_CR21","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.ejmech.2012.09.034","volume":"57","author":"PM Lukasik","year":"2012","unstructured":"Lukasik PM, Elabar S, Lam F, Shao H, Liu X, Abbas AY, et al. Synthesis and biological evaluation of imidazo[4,5-b]pyridine and 4-heteroaryl-pyrimidine derivatives as anti-cancer agents. Eur J Med Chem. 2012;57:311\u201322.","journal-title":"Eur J Med Chem"},{"key":"2056_CR22","doi-asserted-by":"publisher","first-page":"3463","DOI":"10.1016\/j.bmc.2019.06.029","volume":"27","author":"D Drie\u00dfen","year":"2019","unstructured":"Drie\u00dfen D, Stuhldreier F, Frank A, Stark H, Wesselborg S, Stork B, et al. Novel meriolin derivatives as rapid apoptosis inducers. Bioorg Med Chem. 2019;27:3463\u20138.","journal-title":"Bioorg Med Chem"},{"key":"2056_CR23","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1038\/s41416-020-0891-x","volume":"123","author":"MA Skowron","year":"2020","unstructured":"Skowron MA, Vermeulen M, Winkelhausen A, Becker TK, Bremmer F, Petzsch P, et al. CDK4\/6 inhibition presents as a therapeutic option for paediatric and adult germ cell tumours and induces cell cycle arrest and apoptosis via canonical and non-canonical mechanisms. Br J Cancer. 2020;123:378\u201391.","journal-title":"Br J Cancer"},{"key":"2056_CR24","doi-asserted-by":"publisher","first-page":"33","DOI":"10.2174\/2212697X06666190509094514","volume":"6","author":"G Chashoo","year":"2019","unstructured":"Chashoo G, Singh U, Singh PP, Mondhe DM, Vishwakarma RA. A marine-based meriolin (3-pyrimidinylazaindole) derivative (4ab) targets PI3K\/AKT\/mTOR pathway inducing cell cycle arrest and apoptosis in Molt-4 cells. Clin Cancer Drugs. 2019;6:33\u201340.","journal-title":"Clin Cancer Drugs"},{"key":"2056_CR25","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1093\/neuonc\/nou102","volume":"16","author":"M Jarry","year":"2014","unstructured":"Jarry M, Lecointre C, Malleval C, Desrues L, Schouft MT, Lejoncour V, et al. Impact of meriolins, a new class of cyclin-dependent kinase inhibitors, on malignant glioma proliferation and neo-angiogenesis. Neuro Oncol. 2014;16:1484\u201398.","journal-title":"Neuro Oncol."},{"key":"2056_CR26","doi-asserted-by":"publisher","first-page":"4312","DOI":"10.1039\/C6OB00526H","volume":"14","author":"T Thatikonda","year":"2016","unstructured":"Thatikonda T, Singh U, Ambala S, Vishwakarma RA, Singh PP. Metal free C-H functionalization of diazines and related heteroarenes with organoboron species and its application in the synthesis of a CDK inhibitor, meriolin 1. Org Biomol Chem. 2016;14:4312\u201320.","journal-title":"Org Biomol Chem"},{"key":"2056_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2020.115830","volume":"28","author":"DR Motati","year":"2020","unstructured":"Motati DR, Amaradhi R, Ganesh T. Azaindole therapeutic agents. Bioorg Med Chem. 2020;28:115830.","journal-title":"Bioorg Med Chem"},{"key":"2056_CR28","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1038\/s41420-024-01901-y","volume":"10","author":"L Schmitt","year":"2024","unstructured":"Schmitt L, Lechtenberg I, Drie\u00dfen D, Flores-Romero H, Skowron MA, Sekeres M, et al. Novel meriolin derivatives activate the mitochondrial apoptosis pathway in the presence of antiapoptotic Bcl-2. Cell Death Discov. 2024;10:125.","journal-title":"Cell Death Discov."},{"key":"2056_CR29","doi-asserted-by":"crossref","unstructured":"Chu X-J, DePinto W, Bartkovitz D, So S-S, Vu BT, Packman K, et al. Discovery of [4-amino-2-(1-methanesulfonylpi peridin-4-ylamino) pyrimidin-5-yl](2, 3-difluoro-6-methoxyphenyl) methanone (R547), a potent and selective cyclin-dependent kinase inhibitor with significant in vivo antitumor activity. J Med Chem. 2006;49:6549\u201360.","DOI":"10.1021\/jm0606138"},{"key":"2056_CR30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.semcancer.2017.05.011","volume":"48","author":"AE Leroux","year":"2018","unstructured":"Leroux AE, Schulze JO, Biondi RM. AGC kinases, mechanisms of regulation and innovative drug development. Semin Cancer Biol. 2018;48:1\u201317.","journal-title":"Semin Cancer Biol."},{"key":"2056_CR31","doi-asserted-by":"publisher","first-page":"23847","DOI":"10.1074\/jbc.M107890200","volume":"277","author":"MC Morris","year":"2002","unstructured":"Morris MC, Gondeau C, Tainer JA, Divita G. Kinetic mechanism of activation of the Cdk2\/cyclin A complex: key role of the C-lobe of the Cdk. J Biol Chem. 2002;277:23847\u201353.","journal-title":"J Biol Chem"},{"key":"2056_CR32","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1002\/(SICI)1097-0134(19990101)34:1<4::AID-PROT2>3.0.CO;2-6","volume":"34","author":"BK Shoichet","year":"1999","unstructured":"Shoichet BK, Leach AR, Kuntz ID. Ligand solvation in molecular docking. Proteins Struct Funct Bioinforma. 1999;34:4\u201316.","journal-title":"Proteins Struct Funct Bioinforma"},{"key":"2056_CR33","doi-asserted-by":"publisher","first-page":"4540","DOI":"10.1021\/jm960402a","volume":"39","author":"U Schulze-Gahmen","year":"1996","unstructured":"Schulze-Gahmen U, De Bondt HL, Kim S-H. High-resolution crystal structures of human cyclin-dependent kinase 2 with and without ATP: bound waters and natural ligand as guides for inhibitor design. J Med Chem. 1996;39:4540\u20136.","journal-title":"J Med Chem"},{"key":"2056_CR34","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1016\/j.chembiol.2010.09.010","volume":"17","author":"LM Wodicka","year":"2010","unstructured":"Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, et al. Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol. 2010;17:1241\u20139.","journal-title":"Chem Biol"},{"key":"2056_CR35","doi-asserted-by":"publisher","first-page":"2189","DOI":"10.1021\/acs.jcim.0c00057","volume":"60","author":"H Guterres","year":"2020","unstructured":"Guterres H, Im W. Improving protein-ligand docking results with high-throughput molecular dynamics simulations. J Chem Inf Model. 2020;60:2189\u201398.","journal-title":"J Chem Inf Model"},{"key":"2056_CR36","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.02872","volume":"3","author":"AM Narasimha","year":"2014","unstructured":"Narasimha AM, Kaulich M, Shapiro GS, Choi YJ, Sicinski P, Dowdy SF. Cyclin D activates the Rb tumor suppressor by mono-phosphorylation. eLife. 2014;3:e02872.","journal-title":"eLife."},{"key":"2056_CR37","doi-asserted-by":"publisher","first-page":"1960","DOI":"10.3390\/ijms21061960","volume":"21","author":"L Ding","year":"2020","unstructured":"Ding L, Cao J, Lin W, Chen H, Xiong X, Ao H, et al. The roles of cyclin-dependent kinases in cell-cycle progression and therapeutic strategies in human breast cancer. Int J Mol Sci. 2020;21:1960.","journal-title":"Int J Mol Sci"},{"key":"2056_CR38","doi-asserted-by":"publisher","first-page":"12738","DOI":"10.1074\/jbc.272.19.12738","volume":"272","author":"T Zarkowska","year":"1997","unstructured":"Zarkowska T, Mittnacht S. Differential phosphorylation of the retinoblastoma protein by G1\/S cyclin-dependent kinases. J Biol Chem. 1997;272:12738\u201346.","journal-title":"J Biol Chem"},{"key":"2056_CR39","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1128\/MCB.19.2.1068","volume":"19","author":"PD Adams","year":"1999","unstructured":"Adams PD, Li X, Sellers WR, Baker KB, Leng X, Harper JW, et al. Retinoblastoma protein contains a C-terminal motif that targets it for phosphorylation by cyclin-cdk complexes. Mol Cell Biol. 1999;19:1068\u201380.","journal-title":"Mol Cell Biol"},{"key":"2056_CR40","doi-asserted-by":"publisher","first-page":"179","DOI":"10.3390\/cancers7010179","volume":"7","author":"M Peyressatre","year":"2015","unstructured":"Peyressatre M, Pr\u00e9vel C, Pellerano M, Morris MC. Targeting cyclin-dependent kinases in human cancers: from small molecules to peptide inhibitors. Cancers. 2015;7:179\u2013237.","journal-title":"Cancers"},{"key":"2056_CR41","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/0022-1759(91)90198-O","volume":"139","author":"I Nicoletti","year":"1991","unstructured":"Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 1991;139:271\u20139.","journal-title":"J Immunol Methods"},{"key":"2056_CR42","doi-asserted-by":"publisher","first-page":"3834","DOI":"10.1073\/pnas.91.9.3834","volume":"91","author":"X Grana","year":"1994","unstructured":"Grana X, De Luca A, Sang N, Fu Y, Claudio P, Rosenblatt J, et al. PITALRE, a nuclear CDC2-related protein kinase that phosphorylates the retinoblastoma protein in vitro. Proc Natl Acad Sci USA 1994;91:3834\u20138.","journal-title":"Proc Natl Acad Sci USA"},{"key":"2056_CR43","doi-asserted-by":"publisher","first-page":"5165","DOI":"10.1128\/MCB.23.15.5165-5173.2003","volume":"23","author":"J Garriga","year":"2003","unstructured":"Garriga J, Bhattacharya S, Calb\u00f3 J, Marshall RM, Truongcao M, Haines DS, et al. CDK9 is constitutively expressed throughout the cell cycle, and its steady-state expression is independent of SKP2. Mol Cell Biol. 2003;23:5165\u201373.","journal-title":"Mol Cell Biol"},{"key":"2056_CR44","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.678559","volume":"11","author":"AT Anshabo","year":"2021","unstructured":"Anshabo AT, Milne R, Wang S, Albrecht H. CDK9: a comprehensive review of its biology, and its role as a potential target for anti-cancer agents. Front Oncol. 2021;11:678559.","journal-title":"Front Oncol"},{"key":"2056_CR45","doi-asserted-by":"publisher","DOI":"10.1038\/srep42717","volume":"7","author":"A Daina","year":"2017","unstructured":"Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717.","journal-title":"Sci Rep"},{"key":"2056_CR46","doi-asserted-by":"publisher","first-page":"1770","DOI":"10.1200\/JCO.2005.03.7689","volume":"24","author":"GI Shapiro","year":"2006","unstructured":"Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006;24:1770\u201383.","journal-title":"J Clin Oncol"},{"key":"2056_CR47","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1158\/1078-0432.CCR-08-1543","volume":"15","author":"MY Zhao","year":"2009","unstructured":"Zhao MY, Auerbach A, D\u2019Costa AM, Rapoport AP, Burger AM, Sausville EA, et al. Phospho-p70S6K\/p85S6K and cdc2\/cdk1 are novel targets for diffuse large B-cell lymphoma combination therapy. Clin Cancer Res. 2009;15:1708\u201320.","journal-title":"Clin Cancer Res"},{"key":"2056_CR48","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/nrd2907","volume":"8","author":"S Lapenna","year":"2009","unstructured":"Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009;8:547\u201366.","journal-title":"Nat Rev Drug Discov"},{"key":"2056_CR49","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1016\/j.ceb.2013.08.004","volume":"25","author":"C Bruy\u00e8re","year":"2013","unstructured":"Bruy\u00e8re C, Meijer L. Targeting cyclin-dependent kinases in anti-neoplastic therapy. Curr Opin Cell Biol. 2013;25:772\u20139.","journal-title":"Curr Opin Cell Biol"},{"key":"2056_CR50","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1038\/nm1606","volume":"13","author":"A Goga","year":"2007","unstructured":"Goga A, Yang D, Tward AD, Morgan DO, Bishop JM. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat Med. 2007;13:820\u20137.","journal-title":"Nat Med"},{"key":"2056_CR51","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.1038\/sj.onc.1209202","volume":"25","author":"J Yuan","year":"2006","unstructured":"Yuan J, Kr\u00e4mer A, Matthess Y, Yan R, Sp\u00e4nkuch B, G\u00e4tje R, et al. Stable gene silencing of cyclin B1 in tumor cells increases susceptibility to taxol and leads to growth arrest in vivo. Oncogene. 2006;25:1753\u201362.","journal-title":"Oncogene."},{"key":"2056_CR52","doi-asserted-by":"publisher","first-page":"e49","DOI":"10.1093\/nar\/gkm053","volume":"35","author":"MC Morris","year":"2007","unstructured":"Morris MC, Gros E, Aldrian-Herrada G, Choob M, Archdeacon J, Heitz F, et al. A non-covalent peptide-based carrier for in vivo delivery of DNA mimics. Nucleic Acids Res. 2007;35:e49.","journal-title":"Nucleic Acids Res"},{"key":"2056_CR53","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-8-391","volume":"8","author":"I Androic","year":"2008","unstructured":"Androic I, Kr\u00e4mer A, Yan R, R\u00f6del F, G\u00e4tje R, Kaufmann M, et al. Targeting cyclin B1 inhibits proliferation and sensitizes breast cancer cells to taxol. BMC Cancer. 2008;8:391.","journal-title":"BMC Cancer"},{"key":"2056_CR54","doi-asserted-by":"publisher","first-page":"4559","DOI":"10.1093\/nar\/gkp451","volume":"37","author":"L Crombez","year":"2009","unstructured":"Crombez L, Morris MC, Dufort S, Aldrian-Herrada G, Nguyen Q, Mc Master G, et al. Targeting cyclin B1 through peptide-based delivery of siRNA prevents tumour growth. Nucleic Acids Res. 2009;37:4559\u201369.","journal-title":"Nucleic Acids Res"},{"key":"2056_CR55","doi-asserted-by":"publisher","first-page":"5320","DOI":"10.1158\/1078-0432.CCR-13-0259","volume":"19","author":"KE Sheppard","year":"2013","unstructured":"Sheppard KE, McArthur GA. The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin Cancer Res. 2013;19:5320\u20138.","journal-title":"Clin Cancer Res"},{"key":"2056_CR56","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.ccr.2010.05.025","volume":"18","author":"M Puyol","year":"2010","unstructured":"Puyol M, Mart\u00edn A, Dubus P, Mulero F, Pizcueta P, Khan G, et al. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell. 2010;18:63\u201373.","journal-title":"Cancer Cell."},{"key":"2056_CR57","doi-asserted-by":"publisher","first-page":"14897","DOI":"10.18632\/oncotarget.14689","volume":"8","author":"A Alexander","year":"2017","unstructured":"Alexander A, Karakas C, Chen X, Carey JP, Yi M, Bondy M, et al. Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer. Oncotarget. 2017;8:14897\u2013911.","journal-title":"Oncotarget."},{"key":"2056_CR58","doi-asserted-by":"publisher","first-page":"3377","DOI":"10.1158\/0008-5472.CAN-10-4086","volume":"71","author":"S Akli","year":"2011","unstructured":"Akli S, Van Pelt CS, Bui T, Meijer L, Keyomarsi K. Cdk2 is required for breast cancer mediated by the low-molecular-weight isoform of cyclin E. Cancer Res. 2011;71:3377\u201386.","journal-title":"Cancer Res."},{"key":"2056_CR59","doi-asserted-by":"publisher","first-page":"307","DOI":"10.2174\/1573406415666190626113900","volume":"16","author":"J Mou","year":"2020","unstructured":"Mou J, Chen D, Deng Y. Inhibitors of cyclin-dependent kinase 1\/2 for anticancer treatment. Med Chem. 2020;16:307\u201325.","journal-title":"Med Chem."},{"key":"2056_CR60","doi-asserted-by":"publisher","first-page":"4818","DOI":"10.1016\/j.bmcl.2006.06.073","volume":"16","author":"S Huang","year":"2006","unstructured":"Huang S, Li R, Connolly PJ, Emanuel S, Middleton SA. Synthesis of 2-amino-4-(7-azaindol-3-yl) pyrimidines as cyclin dependent kinase 1 (CDK1) inhibitors. Bioorg Med Chem Lett. 2006;16:4818\u201321.","journal-title":"Bioorg Med Chem Lett"},{"key":"2056_CR61","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-018-0574-3","volume":"18","author":"KL Uhl","year":"2018","unstructured":"Uhl KL, Schultz CR, Geerts D, Bachmann AS. Harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor induces caspase-mediated apoptosis in neuroblastoma. Cancer Cell Int. 2018;18:82.","journal-title":"Cancer Cell Int"},{"key":"2056_CR62","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.36656","volume":"7","author":"W Pitsawong","year":"2018","unstructured":"Pitsawong W, Buosi V, Otten R, Agafonov RV, Zorba A, Kern N, et al. Dynamics of human protein kinase Aurora A linked to drug selectivity. eLife. 2018;7:e36656.","journal-title":"eLife."},{"key":"2056_CR63","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1126\/science.aaa1823","volume":"347","author":"C Wilson","year":"2015","unstructured":"Wilson C, Agafonov R, Hoemberger M, Kutter S, Zorba A, Halpin J, et al. Kinase dynamics. Using ancient protein kinases to unravel a modern cancer drug\u2019s mechanism. Science. 2015;347:882\u20136.","journal-title":"Science."},{"key":"2056_CR64","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1038\/sj.cdd.4400938","volume":"8","author":"JYJ Wang","year":"2001","unstructured":"Wang JYJ. DNA damage and apoptosis. Cell Death Differ. 2001;8:1047\u20138.","journal-title":"Cell Death Differ."},{"key":"2056_CR65","doi-asserted-by":"publisher","first-page":"e86709","DOI":"10.1371\/journal.pone.0086709","volume":"9","author":"T Hattori","year":"2014","unstructured":"Hattori T, Uchida C, Takahashi H, Yamamoto N, Naito M, Taya Y. Distinct and site-specific phosphorylation of the retinoblastoma protein at serine 612 in differentiated cells. PLoS ONE. 2014;9:e86709.","journal-title":"PLoS ONE"},{"key":"2056_CR66","first-page":"2925","volume":"5","author":"GI Shapiro","year":"1999","unstructured":"Shapiro GI, Koestner DA, Matranga CB, Rollins BJ. Flavopiridol induces cell cycle arrest and p53-independent apoptosis in non-small cell lung cancer cell lines. Clin Cancer Res. 1999;5:2925\u201338.","journal-title":"Clin Cancer Res"},{"key":"2056_CR67","doi-asserted-by":"publisher","first-page":"4348","DOI":"10.1002\/cam4.2324","volume":"8","author":"H Zhao","year":"2019","unstructured":"Zhao H, Li S, Wang G, Zhao W, Zhang D, Wang F, et al. Study of the mechanism by which dinaciclib induces apoptosis and cell cycle arrest of lymphoma Raji cells through a CDK1-involved pathway. Cancer Med. 2019;8:4348\u201358.","journal-title":"Cancer Med"},{"key":"2056_CR68","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/S1097-2765(03)00526-4","volume":"13","author":"Z Ni","year":"2004","unstructured":"Ni Z, Schwartz BE, Werner J, Suarez J-R, Lis JT. Coordination of transcription, RNA processing, and surveillance by P-TEFb kinase on heat shock genes. Mol Cell. 2004;13:55\u201365.","journal-title":"Mol Cell"},{"key":"2056_CR69","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1101\/gad.999002","volume":"16","author":"EY Shim","year":"2002","unstructured":"Shim EY, Walker AK, Shi Y, Blackwell TK. CDK-9\/cyclin T (P-TEFb) is required in two postinitiation pathways for transcription in the C. elegans embryo. Genes Dev. 2002;16:2135\u201346.","journal-title":"Genes Dev"},{"key":"2056_CR70","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1846","volume":"3","author":"N Czudnochowski","year":"2012","unstructured":"Czudnochowski N, B\u00f6sken CA, Geyer M. Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition. Nat Commun. 2012;3:842.","journal-title":"Nat Commun"},{"key":"2056_CR71","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1038\/leu.2015.10","volume":"29","author":"GP Gregory","year":"2015","unstructured":"Gregory GP, Hogg SJ, Kats LM, Vidacs E, Baker AJ, Gilan O, et al. CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo. Leukemia. 2015;29:1437\u201341.","journal-title":"Leukemia."},{"key":"2056_CR72","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1158\/1078-0432.CCR-19-1853","volume":"26","author":"J Cidado","year":"2020","unstructured":"Cidado J, Boiko S, Proia T, Ferguson D, Criscione SW, San Martin M, et al. AZD4573 is a highly selective CDK9 inhibitor that suppresses MCL-1 and induces apoptosis in hematologic cancer cells. Clin Cancer Res. 2020;26:922\u201334.","journal-title":"Clin Cancer Res"},{"key":"2056_CR73","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/cdd.2013.179","volume":"21","author":"J Lemke","year":"2014","unstructured":"Lemke J, von Karstedt S, Abd El Hay M, Conti A, Arce F, Montinaro A, et al. Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1. Cell Death Differ. 2014;21:491\u2013502.","journal-title":"Cell Death Differ"},{"key":"2056_CR74","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1101\/gad.1304105","volume":"19","author":"SN Willis","year":"2005","unstructured":"Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 2005;19:1294\u2013305.","journal-title":"Genes Dev"},{"key":"2056_CR75","doi-asserted-by":"publisher","first-page":"1270","DOI":"10.1038\/ncb3236","volume":"17","author":"H-C Chen","year":"2015","unstructured":"Chen H-C, Kanai M, Inoue-Yamauchi A, Tu H-C, Huang Y, Ren D, et al. An interconnected hierarchical model of cell death regulation by the BCL-2 family. Nat Cell Biol. 2015;17:1270\u201381.","journal-title":"Nat Cell Biol"},{"key":"2056_CR76","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.1158\/1535-7163.MCT-16-0031","volume":"15","author":"RS Soderquist","year":"2016","unstructured":"Soderquist RS, Eastman A. BCL2 inhibitors as anticancer drugs: a plethora of misleading BH3 mimetics. Mol Cancer Ther. 2016;15:2011\u20137.","journal-title":"Mol Cancer Ther"},{"key":"2056_CR77","volume":"2013","author":"G Romano","year":"2013","unstructured":"Romano G. Deregulations in the cyclin-dependent kinase-9-related pathway in cancer: implications for drug discovery and development. ISRN Oncol. 2013;2013:305371.","journal-title":"ISRN Oncol."},{"key":"2056_CR78","doi-asserted-by":"publisher","first-page":"3015","DOI":"10.1200\/JCO.2009.26.1347","volume":"28","author":"WG Tong","year":"2010","unstructured":"Tong WG, Chen R, Plunkett W, Siegel D, Sinha R, Harvey RD, et al. Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. J Clin Oncol. 2010;28:3015\u201322.","journal-title":"J Clin Oncol"},{"key":"2056_CR79","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1002\/path.1588","volume":"203","author":"C Bellan","year":"2004","unstructured":"Bellan C, De Falco G, Lazzi S, Micheli P, Vicidomini S, Sch\u00fcrfeld K, et al. CDK9\/CYCLIN T1 expression during normal lymphoid differentiation and malignant transformation. J Pathol. 2004;203:946\u201352.","journal-title":"J Pathol"},{"key":"2056_CR80","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2021.100914","volume":"2","author":"T Roider","year":"2021","unstructured":"Roider T, Brinkmann BJ, Dietrich S. Processing human lymph node samples for single-cell assays. STAR Protoc. 2021;2:100914.","journal-title":"STAR Protoc"},{"key":"2056_CR81","doi-asserted-by":"publisher","DOI":"10.15252\/msb.202110855","volume":"18","author":"PM Bruch","year":"2022","unstructured":"Bruch PM, Giles HA, Kolb C, Herbst SA, Becirovic T, Roider T, et al. Drug\u2010microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL. Mol Syst Biol. 2022;18:e10855.","journal-title":"Mol Syst Biol"},{"key":"2056_CR82","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","volume":"27","author":"GM Sastry","year":"2013","unstructured":"Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des. 2013;27:221\u201334.","journal-title":"J Comput Aided Mol Des"},{"key":"2056_CR83","doi-asserted-by":"publisher","first-page":"3333","DOI":"10.1002\/prot.23113","volume":"79","author":"MHM Olsson","year":"2011","unstructured":"Olsson MHM. Protein electrostatics and pKa blind predictions; contribution from empirical predictions of internal ionizable residues. Proteins Struct Funct Bioinforma. 2011;79:3333\u201345.","journal-title":"Proteins Struct Funct Bioinforma"},{"key":"2056_CR84","doi-asserted-by":"crossref","unstructured":"Repasky MP, Shelley M, Friesner RA. Flexible ligand docking with Glide. Curr Protoc Bioinformatics. 2007;Chapter 8:Unit 8.12.","DOI":"10.1002\/0471250953.bi0812s18"},{"key":"2056_CR85","unstructured":"Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al. Gaussian 16 Rev. C.01. Wallingford, CT: Gaussian, Inc; 2016."},{"key":"2056_CR86","doi-asserted-by":"publisher","first-page":"6183","DOI":"10.1021\/acs.jcim.3c01153","volume":"63","author":"DA Case","year":"2023","unstructured":"Case DA, Aktulga HM, Belfon K, Cerutti DS, Cisneros GA, Cruzeiro VWD, et al. AmberTools. J Chem Inf Model. 2023;63:6183\u201391.","journal-title":"J Chem Inf Model"},{"key":"2056_CR87","doi-asserted-by":"publisher","first-page":"3878","DOI":"10.1021\/ct400314y","volume":"9","author":"R Salomon-Ferrer","year":"2013","unstructured":"Salomon-Ferrer R, G\u00f6tz AW, Poole D, Le Grand S, Walker RC. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. Explicit solvent particle mesh Ewald. J Chem Theory Comput. 2013;9:3878\u201388.","journal-title":"J Chem Theory Comput"},{"key":"2056_CR88","doi-asserted-by":"publisher","first-page":"3084","DOI":"10.1021\/ct400341p","volume":"9","author":"DR Roe","year":"2013","unstructured":"Roe DR, Cheatham TE III. PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J Chem Theory Comput. 2013;9:3084\u201395.","journal-title":"J Chem Theory Comput"}],"container-title":["Cell Death Discovery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41420-024-02056-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41420-024-02056-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41420-024-02056-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T13:21:30Z","timestamp":1718112090000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41420-024-02056-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,11]]},"references-count":88,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["2056"],"URL":"https:\/\/doi.org\/10.1038\/s41420-024-02056-6","relation":{},"ISSN":["2058-7716"],"issn-type":[{"value":"2058-7716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,11]]},"assertion":[{"value":"24 April 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 May 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 June 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Informed consent was obtained from all patients before isolation and storage of primary tumor cells in line with the Declaration of Helsinki and the Department of Health and Human Services Belmont Report. The study was approved by the ethics committee of the Medical Faculty Heidelberg, Germany (S-206\/2011 and S-356\/2013).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"279"}}