biostudies-literatureYang JGovernment of Guangdong ProvinceNational Natural Science Foundation of ChinaNational Cancer InstituteNCI NIH HHSProstate Cancer FoundationNational Institutes of HealthLIVZON pharm11066-11083https://www.ebi.ac.uk/biostudies/studies/S-EPMC9876424biostudies-literatureUnknown65(16)Selective degradation of the cyclin-dependent kinases 12 and 13 (CDK12/13) presents a novel therapeutic opportunity for triple-negative breast cancer (TNBC), but there is still a lack of dual CDK12/13 degraders. Here, we report the discovery of the first series of highly potent and selective dual CDK12/13 degraders by employing the proteolysis-targeting chimera (PROTAC) technology. The optimal compound 7f effectively degraded CDK12 and CDK13 with DC50 values of 2.2 and 2.1 nM, respectively, in MDA-MB-231 breast cancer cells. Global proteomic profiling demonstrated the target selectivity of 7f. In vitro, 7f suppressed expression of core DNA damage response (DDR) genes in a time- and dose-dependent manner. Further, 7f markedly inhibited proliferation of multiple TNBC cell lines including MFM223, with an IC50 value of 47 nM. Importantly, 7f displayed a significantly improved antiproliferative activity compared to the structurally similar inhibitor 4, suggesting the potential advantage of a CDK12/13 degrader for TNBC targeted therapy.Journal of medicinal chemistryDiscovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13.PMC987642481903424R35 CA231996P50 CA18678621-PAF01442AWD0164792018B030337001R35CA23199681874284818201080292019A151501068822037003P50CA1867862021A0505020014Tien JCYang JWang CZeng VZVo JZhou YChang YDing KCheng YZhang PWang GXChinnaiyan AMLi SHuang WWang ZApel IJfalseDiscovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13.Selective degradation of the cyclin-dependent kinases 12 and 13 (CDK12/13) presents a novel therapeutic opportunity for triple-negative breast cancer (TNBC), but there is still a lack of dual CDK12/13 degraders. Here, we report the discovery of the first series of highly potent and selective dual CDK12/13 degraders by employing the proteolysis-targeting chimera (PROTAC) technology. The optimal compound 7f effectively degraded CDK12 and CDK13 with DC50 values of 2.2 and 2.1 nM, respectively, in MDA-MB-231 breast cancer cells. Global proteomic profiling demonstrated the target selectivity of 7f. In vitro, 7f suppressed expression of core DNA damage response (DDR) genes in a time- and dose-dependent manner. Further, 7f markedly inhibited proliferation of multiple TNBC cell lines including MFM223, with an IC50 value of 47 nM. Importantly, 7f displayed a significantly improved antiproliferative activity compared to the structurally similar inhibitor 4, suggesting the potential advantage of a CDK12/13 degrader for TNBC targeted therapy.2022-01-01T00:00:00Z2022 Aug2026-05-28T11:32:21.339Z2025-04-07T03:17:01.484ZS-EPMC98764243593850810.1021/acs.jmedchem.2c00384