Major Finding: The novel CDK12/13 inhibitor SR-4835 was effective in mouse models of triple-negative breast cancer.
Concept: SR-4835 is highly selective for CDK12/13 and synergizes with DNA-damaging agents.
Impact: Continued investigation of SR-4835 in triple-negative breast cancer is warranted.

Some triple-negative breast cancers (TNBC) with mutations affecting homologous recombination, such as mutations in BRCA1, are sensitive to treatment with poly (ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapies; however, relapse is common with advanced disease. Quereda and colleagues report the development of the orally bioavailable CDK12/13 inhibitor SR-4835, an agent that may have potential for treatment of TNBC. The compound was developed using structure-guided optimization based on the most selective known inhibitor of CDK12/13, and biochemical assays using a panel of more than 450 kinases demonstrated that SR-4835 is highly selective for CDK12/13, with a half-maximal effective concentration of 100 nM. Further, TNBC cell lines exhibited sensitivity to low-nanomolar concentrations of the drug, and treatment resulted in an increase in DNA damage and apoptosis. Genetic inactivation of CDK12 or CDK13 resulted in a similar phenotype. RNA-sequencing experiments using cells treated with SR-4835 demonstrated that the drug caused downregulation of genes involved in DNA repair and recombination and upregulation of genes involved in cell-cycle progression and apoptosis. Accordingly, SR-4835 synergized with DNA-damaging agents and PARP inhibitors to inhibit cancer cell growth. Experiments using a patient-derived xenograft (PDX) model of TNBC showed that treatment with cisplatin or SR-4835 decreased tumor growth, and combination treatment with SR-4835 and cisplatin resulted in rapid tumor regression without apparent gross toxicity. In a second PDX model, similar results were observed following combination treatment with SR-4835 and irinotecan. Collectively, these findings suggest that SR-4835 is a promising early-stage drug worthy of further investigation in TNBC.
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