生命科学联合中心学术报告

题目：From serendipity to clinical trials:  discovery of reversible covalent kinase inhibitors

报告人：Jack Taunton, Ph.D.

Professor, University of California, San Francisco

时间：2015-4-16（周四），13:00-14:00pm

地点：北京大学邓祐才报告厅

联系人：雷晓光

The clinical utility of targeting kinases with covalent drugs has been firmly established, exemplified by the recent FDA approval of the irreversible kinase inhibitors, afatinib and ibrutinib. More broadly, chemical probes that form a covalent bond with a nonconserved, noncatalytic cysteine often show enhanced potency, selectivity, and utility in biological studies. Despite these advantages, protein-reactive compounds are usually avoided in drug discovery efforts. Motivated by a desire to explore the chemistry of reactive electrophiles and thiols under physiological conditions, we initiated a study of Michael acceptors bearing substituents with increasing electron withdrawing capacity. We were surprised to find that 2-cyanoacrylamides react with simple thiols to form highly unstable adducts. We hypothesized that the intrinsically labile nature of the cysteine/cyanoacrylamide bond could be exploited to yield cysteine-targeted, reversible covalent inhibitors. These concepts have led to the design of ultra-selective kinase inhibitors with slow dissociation kinetics. Clinical trials are underway with one such inhibitor.

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