Synthesis and Target Identification of a Novel Electrophilic Warhead, 2-Chloromethylquinoline

Despite its power in identifying highly potent ligands for select protein targets, conventional medicinal chemistry is limited by its low throughput and lack of proteomic selectivity information. We seek to develop a chemoproteomic approach for discovering covalent ligands for protein targets in an unbiased, high-throughput manner. Tripartite probe compounds composed of a heterocyclic core, an electrophilic "warhead", and an alkyne tag have been designed and synthesized for covalently labeling and identifying targets in cells. We have developed a novel condensation reaction to prepare 2-chloromethylquinoline (2-CMQ), an electrophilic heterocycle. These chloromethylquinolines potently and covalently bind to a number of cellular protein targets, including prostaglandin E synthase 2 (PTGES2), a critical regulator of cell proliferation, apoptosis, angiogenesis, inflammation, and immune surveillance. The 2-CMQs that we have developed here are novel PTGES2 binders that have the potential to serve as therapies for the treatment of human diseases such as inflammation.