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

DOI: 10.1021/jacs.6b05483 DOI Help

Authors: Alvin Kung (University of Southern California) , Ying-Chu Chen (University of Southern California) , Marianne Schimpl (AstraZeneca) , Feng Ni (University of Southern California) , Jianfa Zhu (University of Southern California) , Maurice Turner (University of Southern California) , Henrik Molina (The Rockefeller University) , Ross Overman (AstraZeneca) , Chao Zhang (of Southern California)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of The American Chemical Society , VOL 138 , PAGES 10554 - 10560

State: Published (Approved)
Published: August 2016

Abstract: Erythropoietin-producing human hepatocellular carcinoma (Eph) receptor tyrosine kinases (RTKs) regulate a variety of dynamic cellular events, including cell protrusion, migration, proliferation, and cell-fate determination. 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 specific inhibitors of a single 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 in vitro and in cells. Cocrystal structures of EphB3 in complex with two quinazolines confirmed the covalent linkage between the protein and the inhibitors. A “clickable” version of an optimized inhibitor was created and employed to verify specific target engagement in the whole proteome and to probe the extent and kinetics of target engagement of existing EphB3 inhibitors. Furthermore, we demonstrate that the autophosphorylation of EphB3 within the juxtamembrane region occurs in trans using a specific inhibitor. These exquisitely specific inhibitors will facilitate the dissection of EphB3’s role in various biological processes and disease contribution.

Journal Keywords: Peptides and proteins; Monomers; Inhibitors; Inhibition; Receptors

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 21/04/2017 14:53

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)