SR-5037

SR-5037 is an orally active inhibitor of CDK12 (IC50 = 31 nM) and CDK13, as well as a molecular glue degrader for CycK [DC50 = 30 nM; Dmax > 98%]. It suppresses the enzymatic activity of CDK12/CycK and CDK13/CycK complexes. SR-5037 facilitates the recruitment of DDB1 to the CDK12/CycK complex, triggering proteasome-mediated degradation of CycK. In triple-negative breast cancer mouse models, SR-5037 degrades CycK activity. This compound is potentially useful for cancer research, including triple-negative breast cancer.

CDK12:31 nM

SR-5037 at a concentration of 1μM inhibits the enzyme activities of WEE1 (59.8%), mTOR (50.6%), and CDK15 (49.2%). When used at concentrations between 0.000001-10 μM for 2 hours at room temperature, it suppresses the enzymatic activity of human CDK12/CycK, with an IC50 of 58.7 nM and a Kd of 139 nM, as well as CDK13/CycK, with an IC50 of 134.6 nM. Additionally, SR-5037 facilitates the formation of a stable ternary complex between CDK12/CycK and DDB1 (Kd = 2.81 nM). At 100 nM for 1-4 hours, this compound induces potent and rapid degradation of CycK in MDA-MB-231 cells. Furthermore, a 2-hour treatment in HiBiT-CycK knock-in A549 cells leads to cyclin K degradation, with a DC50 of 30 nM and Dmax exceeding 95%.

SR-5037 (2-18 mg/kg; p.o.; single dose) induces dose-dependent depletion of CycK in triple-negative breast cancer tumors in NSG mice.