Identification of an allosteric benzothiazolopyrimidone inhibitor of the oncogenic protein tyrosine phosphatase SHP2

Bioorganic & Medicinal Chemistry
Jonathan R LaRochelleStephen C Blacklow

Abstract

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.

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Citations

Dec 7, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Panagiotis ParsonidisIoannis Papasotiriou
Oct 13, 2020·The Journal of Experimental Medicine·Carmine FedeleBenjamin G Neel
Nov 17, 2020·Chemical Biology & Drug Design·Rati Kailash Prasad Tripathi, Senthil Raja Ayyannan
Mar 12, 2021·Bioorganic Chemistry·Mengzhu ZhengHua Li
Mar 17, 2021·The Journal of Biological Chemistry·Youqi TaoCong Liu
Jan 29, 2019·Journal of Medicinal Chemistry·Patrick SarverMatthew J LaMarche
Jan 6, 2018·ACS Chemical Biology·Michelle FodorMatthew J LaMarche

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