The design and development of new inhibitor scaffolds that broaden the scope of analog-sensitive kinase technology.

摘要

Engineered analog-sensitive (AS) protein kinases have emerged as powerful tools for dissecting phospho-signaling pathways, for elucidating the cellular function of individual kinases, and for deciphering unanticipated effects of clinical therapeutics. A crucial and necessary feature of this technology is a bioorthogonal small molecule that is innocuous towards native cellular systems but can potently inhibit the engineered kinase. In an effort to generalize this method we report the development of two new AS kinase inhibitors. First we describe 3MB-PP1, an inhibitor that targets recalcitrant AS kinases that are not sensitive to other known AS-kinase inhibitors. Second, we report the design and development of a new class of inhibitors, termed staralogs, which are uniquely specific for AS kinases. Staralogs extend the scope of the AS technique to include kinases, such as EphA4, that are sensitive to other AS kinase inhibitors even in their un-engineered Wild-Type (WT) form. Finally, we use lessons learned from the development of staralogs to design a new molecule, Star 23, that is an extremely selective and potent inhibitor of Flt3 kinase, a validated drug target for the treatment of acute myeloid leukemia (AML). We suggest Star 23 may serve as a superior therapeutic agent because it does not target the homologous kinase, c-Kit, whose activity is required for the regeneration of healthy white blood cells necessary for a patient's complete remission.