Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 25, Issue 24, Pages 6479-6485Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.10.025
Keywords
Drug discovery; Structural biology; Allosteric; Inhibitor; Phosphatase; SHP2
Funding
- Novartis-Dana Farber Cancer Institute Drug Development Program [P50 GM10718A1]
- William Lawrence-Blanche Hughes Foundation
- American Cancer Society [128126]
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The PTPN11 oncogene encodes the cytoplasmic protein tyrosine phosphatase SHP2, which, through its role in multiple signaling pathways, promotes the progression of hematological malignancies and other cancers. Here, we employ high-throughput screening to discover a lead chemical scaffold, the benzothiazolopyrimidones, that allosterically inhibits this oncogenic phosphatase by simultaneously engaging the C-SH2 and PTP domains. We improved our lead to generate an analogue that better suppresses SHP2 activity in vitro. Suppression of Erk phopsphorylation by the lead compound is also consistent with SHP2 inhibition in AML cells. Our findings provide an alternative starting point for therapeutic intervention and will catalyze investigations into the relationship between SHP2 conformational regulation, activity, and disease progression. (C) 2017 Elsevier Ltd. All rights reserved.
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