SR-4835 | CDK12/13 inhibitor

SR-4835 (2387704-62-1) is a potent and selective inhibitor of cyclin-dependent kinases 12 and 13 (KD₅₀s: CDK12 = 98 nM, CDK13 = 4.9 nM).¹ It displayed efficacy against multiple triple-negative breast cancer cell lines (EC₅₀s: MDA-MB-231 15.5 nM; MDA-MB-468 22.1 nM; HS578T 19.9 nM; MDA-MB-436 24.9 nM). Inhibition of CDK12/13 with SR-4835 resulted in down-regulation of multiple DNA damage response genes and caused increased DNA damage and apoptosis. SR-4835 acted synergistically with DNA-damaging agents and PARP inhibitors to cause triple-negative breast cancer cell death.^1,2 It acted synergistically with PD-1 blockade to provide a durable immune-mediated antitumor response in a syngeneic breast cancer mouse model.³ SR-4835 has been found to act as a molecular glue that promotes cyclin K degradation.⁴ Inhibition of CDK12 with SR-4835 suppressed tumor initiation and growth in a colorectal cancer mouse model and impaired liver metastasis of colorectal cancer cells while also diminishing cancer stem cell traits through ß-catenin pathway activation.⁵

References/Citations:

1. Quereda et al. (2019), Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer; Cancer Cell 36 P545
2. Orhan et al. (2024); CDK inhibition results I pharmacologic BRCAness increasing sensitivity to olaparib in BRCA1-WT and olaparib resistant Triple Negative Breast Cancer, Cancer Lett., 589 216820
3. Li et al. (2020); CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer, Cancer Lett., 495 12
4. Houles et al. (2023); The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma, Cell Death Discov., 9 459
5. Liu et al. (2023); Targeting CDK12 obviates the malignant phenotypes of colorectal cancer through the Wnt/ß-catenin signaling pathway, Exp. Cell Res., 428 113613