Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy

Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival. Targeting CDK9 has shown potent anti-tumor activity in clinical trials among different cancers. However, the study and knowledge on drug resistance to CDK9 inhibitors are very limited. In this study, we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152. Through genomic sequencing, we identified in the kinase domain of CDK9 a mutation L156F, which is also a coding SNP in the CDK9 gene. By knocking in L156F into cancer cells using CRISPR/Cas9, we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors, not only ATP competitive inhibitor but also PROTAC degrader. Mechanistically, CDK9 L156F disrupts the binding with inhibitors due to steric hindrance, further, the mutation affects the thermal stability and catalytic activity of CDK9 protein. To overcome the drug resistance mediated by the CDK9-L156F mutation, we discovered a compound, IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant. Together, we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.

Advances in research on a novel antitumor target CDK9 and its inhibitors / 中国药科大学学报

The cyclin-dependent protein kinase 9 (CDK9) is a member of the family of cyclin-dependent protein kinases.Different from other CDKs,CDK9 mainly works on the transcription regulation and has no affects on the cell cycle progress.There are many kinds of CDK9 inhibitors in the clinical research.The detailed structure and action mechanism of CDK9,its difference of protein structure from other CDKs,several selective or nonselective CDK9 inhibitors,as well as their structure-activity relationship (SAR) are discussed in this paper.