Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 221, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113481
Keywords
CDK12/13; Covalent inhibitor; Structure-activity relationship
Categories
Funding
- Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy [GE 976/9-2, EXC2151-390873048]
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BSJ-01-175 is the first selective CDK12/13 covalent inhibitor with in vivo efficacy, exhibiting potent inhibition of RNA polymerase II phosphorylation and downregulation of CDK12-targeted genes in cancer cells.
Development of inhibitors targeting CDK12/13 is of increasing interest as a potential therapy for cancers as these compounds inhibit transcription of DNA damage response (DDR) genes. We previously described THZ531, a covalent inhibitor with selectivity for CDK12/13. In order to elucidate structure-activity relationship (SAR), we have undertaken a medicinal chemistry campaign and established a focused library of THZ531 analogs. Among these analogs, BSJ-01-175 demonstrates exquisite selectivity, potent inhibition of RNA polymerase II phosphorylation, and downregulation of CDK12-targeted genes in cancer cells. A 3.0 angstrom co-crystal structure with CDK12/CycK provides a structural rational for selective targeting of Cys1039 located in a C-terminal extension from the kinase domain. With moderate pharmacokinetic properties, BSJ- 01-175 exhibits efficacy against an Ewing sarcoma tumor growth in a patient-derived xenograft (PDX) mouse model following 10 mg/kg once a day, intraperitoneal administration. Taken together, BSJ-01-175 represents the first selective CDK12/13 covalent inhibitor with in vivo efficacy reported to date. (C) 2021 Elsevier Masson SAS. All rights reserved.
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