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Examining the influence of specificity ligands and ATP-competitive ligands on the overall effectiveness of bivalent kinase inhibitors

Murphy, Jason and Harrington, Edmund and Schirle, Markus and Wong, Margaret and Gower, Carrie and Maly, Dustin (2017) Examining the influence of specificity ligands and ATP-competitive ligands on the overall effectiveness of bivalent kinase inhibitors. Proteome science, 15 (17). ISSN 1477-5956

Abstract

Identifying selective kinase inhibitors remains a major challenge. The design of bivalent inhibitors provides a rational strategy for accessing potent and selective kinase inhibitors. While bivalent kinase inhibitors have been successfully designed, no comprehensive assessment of affinity and selectivity for a series of bivalent inhibitors has been performed. Here, we present an evaluation of the structure activity relationship for bivalent kinase inhibitors targeting ABL1. Through unbiased chemical proteomics, this works provides the first insight into the influence of ATP-competitive and specificity ligands binding to their intended target on a proteome-wide scale. The resulting data suggest a subtle interplay between the ATP-competitive and specificity ligand that cannot be accounted for by considering the specificity or affinity of the individual components alone.

Item Type: Article
Date Deposited: 22 Aug 2017 00:45
Last Modified: 22 Aug 2017 00:45
URI: https://oak.novartis.com/id/eprint/32371

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