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.