Dysregulation of kinase signaling pathway can result in a variety of human diseases, particularly cancer. The c-Jun N-terminal kinase (JNK), which belongs to the mitogen-activated protein kinase (MAPK) family has been identified as a therapeutic target for numerous diseases. However, designing small-molecule inhibitors has encountered two major obstacles, target selectivity and drug resistance. In light of overcoming these obstacles, targeted covalent inhibitor design has attracted attention recently. Typically, covalent kinase inhibitors target a nucleophilic cysteine via an electrophilic warhead. In a recent work, we proposed a general strategy for identifying kinome-wide reactive cysteines using a pKa prediction tool based on continuous constant pH molecular dynamics. In this work, we applied the most recent GPU implementation with single-pH titration simulations to examine the nucleophilicities of cysteines in the JNK1, JNK2, and JNK3 kinases for designing irreversible covalent inhibitors. As controls, we investigated the thiol reactivities in two commonly used experimental probes, glutathione and human La antigen. Our study further demonstrates the predictive power of the computational tools for accelerating the rational discovery of new targeted covalent kinase inhibitors.

Nucleophilicities of cysteines in JNK kinases for designing covalent inhibitors

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.