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

Abstract The PTPN11 oncogeneencodes the cytoplasmic protein tyrosine phosphataseSHP2, which, through its role in multiple signaling pathways, promotes the progression of hematological malignanciesand other cancers. Here, we employ high-throughput screeningto discover a lead chemical scaffold, the benzothiazolopyrimidones, that allosterically inhibits this oncogenicphosphatase 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 compoundis 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.