{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Yang J"],"funding":["Government of Guangdong Province","National Natural Science Foundation of China","National Cancer Institute","NCI NIH HHS","Prostate Cancer Foundation","National Institutes of Health","LIVZON pharm"],"pagination":["11066-11083"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9876424"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["65(16)"],"pubmed_abstract":["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 <b>7f</b> effectively degraded CDK12 and CDK13 with DC<sub>50</sub> values of 2.2 and 2.1 nM, respectively, in MDA-MB-231 breast cancer cells. Global proteomic profiling demonstrated the target selectivity of <b>7f</b>. <i>In vitro</i>, <b>7f</b> suppressed expression of core DNA damage response (DDR) genes in a time- and dose-dependent manner. Further, <b>7f</b> markedly inhibited proliferation of multiple TNBC cell lines including MFM223, with an IC<sub>50</sub> value of 47 nM. Importantly, <b>7f</b> displayed a significantly improved antiproliferative activity compared to the structurally similar inhibitor <b>4</b>, suggesting the potential advantage of a CDK12/13 degrader for TNBC targeted therapy."],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Discovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13."],"pmcid":["PMC9876424"],"funding_grant_id":["81903424","R35 CA231996","P50 CA186786","21-PAF01442","AWD016479","2018B030337001","R35CA231996","81874284","81820108029","2019A1515010688","22037003","P50CA186786","2021A0505020014"],"pubmed_authors":["Tien JC","Yang J","Wang C","Zeng VZ","Vo J","Zhou Y","Chang Y","Ding K","Cheng Y","Zhang P","Wang GX","Chinnaiyan AM","Li S","Huang W","Wang Z","Apel IJ"],"additional_accession":[]},"is_claimable":false,"name":"Discovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13.","description":"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 <b>7f</b> effectively degraded CDK12 and CDK13 with DC<sub>50</sub> values of 2.2 and 2.1 nM, respectively, in MDA-MB-231 breast cancer cells. Global proteomic profiling demonstrated the target selectivity of <b>7f</b>. <i>In vitro</i>, <b>7f</b> suppressed expression of core DNA damage response (DDR) genes in a time- and dose-dependent manner. Further, <b>7f</b> markedly inhibited proliferation of multiple TNBC cell lines including MFM223, with an IC<sub>50</sub> value of 47 nM. Importantly, <b>7f</b> displayed a significantly improved antiproliferative activity compared to the structurally similar inhibitor <b>4</b>, suggesting the potential advantage of a CDK12/13 degrader for TNBC targeted therapy.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Aug","modification":"2026-05-28T11:32:21.339Z","creation":"2025-04-07T03:17:01.484Z"},"accession":"S-EPMC9876424","cross_references":{"pubmed":["35938508"],"doi":["10.1021/acs.jmedchem.2c00384"]}}