CDKs are serine/threonine protein kinases. They play major roles in regulating many different aspects of mammalian cellular function, most notably cell cycle and transcription. CDK12 is an emerging therapeutic target due to its role in regulating the transcription of DNA-damage response (DDR) genes. For example, ovarian and triple-negative breast cancer cells with the lower expression of CDK12 are more sensitive to the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, and a combination treatment of olaparib and dinaciclib, a nonselective CDK12 inhibitor, synergistically suppressed tumor growth in PDX models. Therefore, small molecules that selectively target CDK12 are needed to elucidate the biological functions of CDK12 and validate its therapeutic potential. In this study, BSJ-4-116 is a highly potent and selective CDK12 degrader CDK12 degrader with an IC₅₀ of 6 nM. BSJ-4-116 downregulates DDR genes through a premature termination of transcription, primarily through increasing poly(adenylation).

BSJ-4-116 exhibits potent antiproliferative effects in Kelly CDK12^C1039F. It also decreases the level of CDK12 protein, regardless of the mutational status of the cell line. Moreover, it inhibits the growth of T-ALL cells (Jurkat and MOLT-4 cells) and sensitizes them to PARP inhibition. BSJ-4-116 also regulates DDR genes via poly(adenylation). BSJ-4-116 overcomes CDK12^C1039F mutation. Furthermore, BSJ-4-116 represents the first example of resistance to a bivalent degrader molecule. It is a consequence of an acquired point mutation in the target protein.

In summary, BSJ-4-116 selectively degrades CDK12 as assessed through quantitative proteomics. Selective degradation of CDK12 results in premature cleavage and poly(adenylation) of DDR genes. Moreover, BSJ-4-116 exhibits 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.