Larochelle, Jonathan R., Ellegast, Jana M., Fodor, Michelle, Liu, Xiaoxi, Vemulalpalli, Vidyasiri, Mohseni, Mori, Stams, Travis, Lamarche, Matthew, Buhrlage, Sara J., Acker, Michael, Stegmaier, Kimberly and Blacklow, Stephen C. (2017) Identification of an allosteric benzothiazolopyrimidone inhibitor of the oncogenic protein tyrosine phosphatase SHP2. Bioorganic and Medicinal Chemistry, 25 (24). pp. 6479-6485. ISSN 14643391

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.

Item Type:	Article
Keywords:	Allosteric Drug discovery Inhibitor Phosphatase SHP2 Structural biology
Date Deposited:	23 Jan 2018 00:45
Last Modified:	25 Jan 2019 00:45
URI:	https://oak.novartis.com/id/eprint/33163