The Allosteric Site on SHP2's Protein Tyrosine Phosphatase Domain is Targetable with Druglike Small Molecules.

ABSTRACT: Difficulties in developing active-site-directed protein tyrosine phosphatase (PTP) inhibitors have led to the perception that PTPs are "undruggable", highlighting the need for new means to target pharmaceutically important PTPs allosterically. Recently, we characterized an allosteric-inhibition site on the PTP domain of Src-homology-2-domain-containing PTP 2 (SHP2), a key anticancer drug target. The central feature of SHP2's allosteric site is a nonconserved cysteine residue (C333) that can potentially be labeled with electrophilic compounds for selective SHP2 inhibition. Here, we describe the first directed discovery effort for C333-targeted allosteric SHP2 inhibitors. By screening a previously reported library of reversible, covalent inhibitors, we identified a lead compound, which was m

SUBMITTER: Marsh-Armstrong B 

PROVIDER: S-EPMC6275946 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature