Abstract P1-06-03: A selective Cdk12/13 non-covalent inhibitor with potent anti-breast cancer activity

Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) are Ser/Thr protein kinase members of the CDK family. CDKs are regulated by cyclins and members of the family are key regulators of the cell cycle. Other members of this family—CDK7, CDK8, CDK9, CDK12 and CDK13—have been described as transcription-regulating kinases. CDK12 and CDK13 phosphorylate the C-terminal domain (CTD) of rpb1 the largest subunit of RNA polymerase II and interact with RNA processing factors, playing pivotal roles controlling transcription initiation and elongation, as well as posttranscriptional RNA processing. Specifically, CDK12 acts as the limiting factor for the transcription of a small subset of genes that are involved in the DNA damage response pathway and CDK13 affects expression of genes involved in growth signaling pathways. Importantly, like their cell cycle family members CDK12 and CDK13 have also been shown to be promising therapeutic targets for several cancer types. We have generated a novel, selective, and orally bioavailable, small molecule inhibitor of CDK12 and CDK13. Our lead molecule downregulates key DNA damage repair proteins including ATM, ATR, Brca1 and Rad51 leading to induction of apoptotic cell death in all triple negative breast cancer (TNBC) cell lines tested. We have confirmed the selectivity of our compound by kinase profiling and by comparing the gene expression profile by RNA-seq of cells treated with compound or infected with CRISPR sgRNA targeting Cdk12 and/or Cdk13. Importantly, our compound acts in synergy with the chemotherapeutic agents Cisplatin, Irinotecan and Olaparib. Finally, in preclinical efficacy studies, our lead compound blocked tumor progression in two different PDX models of TNBC and demonstrated tumor regression and enhanced efficacy over single treatment when dosed in combination with selected chemotherapeutic agents. Citation Format: Quereda V, Bayle S, Francesca V, Andrii M, William R, Derek D. A selective Cdk12/13 non-covalent inhibitor with potent anti-breast cancer activity [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-03.