Discovery and resistance mechanism of a selective CDK12 degrader

by Selleckchem | Sep 24 2023

Cyclin-dependent kinase 12 (CDK12) is an emerging therapeutic target due to its role in regulating transcription of DNA-damage response (DDR) genes. However, development of selective small molecules targeting CDK12 has been challenging due to the high degree of homology between kinase domains of CDK12 and other transcriptional CDKs, most notably CDK13. In the present study, we report the rational design and characterization of a CDK12-specific degrader, BSJ-4-116. BSJ-4-116 selectively degraded CDK12 as assessed through quantitative proteomics. Selective degradation of CDK12 resulted in premature cleavage and poly(adenylation) of DDR genes. Moreover, BSJ-4-116 exhibited potent antiproliferative effects, alone and in combination with the poly(ADP-ribose) polymerase inhibitor olaparib, as well as when used as a single agent against cell lines resistant to covalent CDK12 inhibitors. Two point mutations in CDK12 were identified that confer resistance to BSJ-4-116, demonstrating a potential mechanism that tumor cells can use to evade bivalent degrader molecules.

Comments:

The study you mentioned focuses on the development of a specific degrader, BSJ-4-116, targeting cyclin-dependent kinase 12 (CDK12). CDK12 is a protein involved in regulating the transcription of genes involved in the DNA-damage response (DDR). The researchers aimed to design a selective small molecule that can target CDK12 without affecting other transcriptional CDKs, particularly CDK13, which shares a high degree of homology with CDK12.

The researchers successfully designed and characterized BSJ-4-116 as a CDK12-specific degrader. They used quantitative proteomics to confirm the selective degradation of CDK12 by BSJ-4-116. The degradation of CDK12 resulted in premature cleavage and poly(adenylation) of DDR genes, indicating disruption of their normal transcriptional regulation.

Furthermore, BSJ-4-116 demonstrated potent antiproliferative effects both as a single agent and in combination with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. This suggests that targeting CDK12 with BSJ-4-116 could be a promising strategy for cancer treatment, potentially enhancing the efficacy of existing therapies such as PARP inhibitors.

Importantly, the researchers also investigated the efficacy of BSJ-4-116 against cancer cell lines that are resistant to covalent CDK12 inhibitors. BSJ-4-116 showed activity against these resistant cell lines, suggesting that it may offer an alternative therapeutic option for patients who do not respond to existing CDK12 inhibitors.

However, the study also identified two point mutations in CDK12 that confer resistance to BSJ-4-116. These mutations provide insights into potential mechanisms that tumor cells can employ to evade the effects of bivalent degrader molecules like BSJ-4-116.

Overall, the study highlights the rational design and characterization of BSJ-4-116 as a CDK12-specific degrader. It demonstrates the potential of selective CDK12 degradation as a therapeutic strategy for cancer treatment, either alone or in combination with other agents, and sheds light on mechanisms of resistance that may arise. Further research and development are needed to explore the clinical implications of CDK12 degradation and its potential as a targeted therapy.