Cyclin dependent kinase 12 (CDK12) has emerged as a target of interest in DNA damage response (DDR) biology. CDK12 plays a role in transcription due to its ability to modify the phosphorylation state of the C-terminal domain (CTD) of RNA polymerase II (RNA pol II). It has been shown that siRNA knockdown or small molecule inhibition of CDK12 (with covalent inhibitor THZ531) results in preferential reduction of expression of DDR associated genes. Furthermore, siRNA knockdown of CDK12 has been shown to sensitize cells to olaparib in vitro, and combination treatment using the covalent CDK12 inhibitor THZ1 with olaparib showed an enhanced effect on tumor growth inhibition. However, since THZ1 is known to inhibit CDK7, we sought to deliver a highly selective, covalent CDK12 inhibitor. Starting with a highly potent purine based scaffold, we were able generate selective covalent CDK12 inhibitors, putatively by engaging Cys1039 on CDK12. Broad kinase panel binding and inhibition assay, along with kinase affinity proteomics data and secondary pharmacology on these purine derived covalent CDK12 inhibitors demonstrate a high degree of selectivity for CDK12. Protein mass spectrometry data supports the hypothesis that our compounds covalently modify CDK12. Furthermore, these compounds are able to inhibit the phosphorylation of serine 2 on the CTD of RNA pol II and show potent growth inhibition of OV90 cells at levels similar to THZ1 and THZ531 with improved selectivity for CDK12.

Highly selective purine based covalent CDK12 inhibitors

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.