SR-4835 (SR4835) is a potent, highly selective dual inhibitor of CDK12 and CDK13 with IC50 of 98 and 4.9 nM, respectively.
SR-4835 is highly selective toward CDK12 and CDK13 when tested in a panel of over 450 kinases at 10 uM, including CDK4, CDK6, CDK9, GSK3A, and GSK3B.
SR-4835 blocks Ser2 phosphorylation on the CTD of RNA Pol II (EC50=100 nM), has no affinity to BRD4 and does not inhibit PARP activity.
SR-4835 blocked clonogenic growth and survival of MDA-MB-231 cells (IC50=15.5 nM) with increased potency over THZ531.
SR-4835 suppressed the expression of DNA damage repair proteins accompanied with increased DNA damage and cell death in tumor cells.
SR-4835 synergizes with DNA-damaging chemotherapeutics cisplatin and provokes TNBC cell death by downregulating DNA repair proteins.
SR-4835/Cisplatin combination provokes tumor regression in an orthotopic TNBC PDX model.
SR-4835/Irinotecan combination provokes regression in BRCA1-deficient PDX model.