Erythropoietin-producing human hepatocellular carcinoma (Eph) receptor tyrosine kinases regulate a variety of dynamic cellular events. Small-molecule inhibitors of Eph kinases are valuable tools for dissecting the physiological and pathological roles of Eph. However, there is a lack of small-molecule inhibitors that are selective for individual Eph isoforms due to the high homology within the family. Herein, we report the development of the first potent and selective inhibitors of one Eph isoform, EphB3. Through structural bioinformatic analysis, we identified a cysteine in the hinge region of the EphB3 kinase domain, a feature that is not shared with any other human kinases. We synthesized and characterized a series of electrophilic quinazolines to target this unique, reactive feature in EphB3. Some of the electrophilic quinazolines selectively and potently inhibited EphB3 both <i>in vitro</i> and in cells. These novel isoform-selective inhibitors will facilitate the dissection of EphB3’s role in biological processes and disease contribution.

Development of selective, irreversible inhibitors for a receptor tyrosine kinase EphB3

251st National Meeting (2016)

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