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

Jonathan R LaRochelle; Michelle Fodor; Jana M Ellegast; Xiaoxi Liu; Vidyasiri Vemulapalli; Morvarid Mohseni; Travis Stams; Sara J Buhrlage; Kimberly Stegmaier; Matthew J LaMarche; Michael G Acker; Stephen C Blacklow

doi:10.1016/j.bmc.2017.10.025

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

Bioorg Med Chem. 2017 Dec 15;25(24):6479-6485. doi: 10.1016/j.bmc.2017.10.025. Epub 2017 Oct 20.

Affiliations

¹ Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
³ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA.
⁴ Center for Oncology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA.
⁶ Center for Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
⁷ Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: stephen_blacklow@hms.harvard.edu.

PMID: 29089257
DOI: 10.1016/j.bmc.2017.10.025

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.

Keywords: Allosteric; Drug discovery; Inhibitor; Phosphatase; SHP2; Structural biology.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation / drug effects
Benzothiazoles / chemical synthesis
Benzothiazoles / chemistry
Benzothiazoles / pharmacology*
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 Kinase Inhibitors / pharmacology*
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry
Pyrimidinones / pharmacology*
Structure-Activity Relationship

Substances

Benzothiazoles
Protein Kinase Inhibitors
Pyrimidinones
benzothiazolopyrimidone
Protein Tyrosine Phosphatase, Non-Receptor Type 11