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A chemical-genetic approach to generate selective covalent inhibitors of protein kinases

DOI: 10.1021/acschembio.6b01083 DOI Help

Authors: Alvin Kung (University of Southern California) , Marianne Schimpl (AstraZeneca) , Arunika Ishani Ekanayake (University of Southern California) , Ying-Chu Chen (University of Southern California) , Ross Overman (AstraZeneca) , Chao Zhang (University of Southern California)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Chemical Biology

State: Published (Approved)
Published: May 2017

Abstract: Although a previously developed bump-hole approach has proven powerful in generating specific inhibitors for mapping functions of protein kinases, its application is limited by the intolerance of the large-to-small mutation by certain kinases and the inability to control two kinases separately in the same cells. Herein, we describe the development of an alternative chemical-genetic approach to overcome these limitations. Our approach features the use of an engineered cysteine residue at a particular position as a reactive feature to sensitize a kinase of interest to selective covalent blockade by electrophilic inhibitors and is thus termed Ele-Cys approach. We successfully applied the Ele-Cys approach to identify selective covalent inhibitors of a receptor tyrosine kinase EphB1, and solved cocrystal structures to determine the mode of covalent binding. Importantly, the Ele-Cys and bump-hole approaches afforded orthogonal inhibition of two distinct kinases in the cell, opening the door to their combined use in the study of multi-kinase signaling pathways.

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

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

Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 08/05/2017 10:50

Discipline Tags:

Health & Wellbeing Biochemistry Genetics Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)