Protein kinases have been pursued as drug targets for more than 20 years, but a significant part of the human “kinome” has not yet been addressed with specific inhibitors, despite its likely medical relevance. Our research focuses on the identification of new covalent inhibitors for both validated and understudied protein kinases.

In our recent work, we and our collaborators have employed rational design approaches as well as intact-protein mass spectrometry (MS) screens to explore kinase-inhibitor-like covalent libraries equipped with cysteine and lysine/tyrosine reactive “warheads”. These efforts have yielded a variety of promising hits. In addition to mass spectrometry, we utilized a suite of complementary methods, including thermal shift assays, biochemical enzyme assays, cellular assays, and X-ray crystallography, for further investigation and thorough validation.

My presentation will detail our progress in extending the range of known protein kinase inhibitors, especially focusing on new inhibitors of lesser-studied kinases. Additionally, I will discuss non-conventional binding modes we have identified, which provide a basis for ongoing medicinal chemistry optimization. These results help to unlock a broader range of kinase targets and support current and future efforts in kinase inhibitor development.