Discovery of novel imidazo[1,2-b]pyridazine derivatives as potent covalent inhibitors of CDK12/13.

Triple-negative breast cancer (TNBC) is widely recognized as the most aggressive subtype of breast cancer, and treatment options for patients with TNBC remain highly limited. Recently, cyclin-dependent kinases 12/13 (CDK12/13) have been identified as promising therapeutic targets for TNBC. In our study, we report the design and synthesis of novel imidazo[1,2-b]pyrazine-based covalent inhibitors of CDK12/13, which exhibit potent inhibitory activity against TNBC cells. Among these compounds, compound 24 emerged as the most potent inhibitor, with CDK12 IC50 of 15.5 nM and CDK13 IC50 of 12.2 nM. Compound 24 forms a covalent bond with Cys1039 of CDK12 and effectively suppresses the proliferation of TNBC cell lines MDA-MB-231 and MDA-MB-468, with EC50 values of 5.0 nM and 6.0 nM, respectively. Compound 24 demonstrated superior efficacy to the currently known CDK12/13 covalent inhibitor, THZ531. These findings suggest compound 24 may be a promising lead for developing CDK12/13-targeted therapies for treating TNBC.