1. Identification of an allosteric benzothiazolopyrimidone inhibitor of the oncogenic protein tyrosine phosphatase SHP2.
- Author
-
LaRochelle JR, Fodor M, Ellegast JM, Liu X, Vemulapalli V, Mohseni M, Stams T, Buhrlage SJ, Stegmaier K, LaMarche MJ, Acker MG, and Blacklow SC
- Subjects
- Allosteric Regulation drug effects, Benzothiazoles chemical synthesis, Benzothiazoles chemistry, Cell Line, Tumor, Cell Survival drug effects, Dose-Response Relationship, Drug, Humans, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism, Pyrimidinones chemical synthesis, Pyrimidinones chemistry, Structure-Activity Relationship, Benzothiazoles pharmacology, Protein Kinase Inhibitors pharmacology, Protein Tyrosine Phosphatase, Non-Receptor Type 11 antagonists & inhibitors, Pyrimidinones pharmacology
- 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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF