Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors

J Med Chem. 2019 Feb 28;62(4):1781-1792. doi: 10.1021/acs.jmedchem.8b01725. Epub 2019 Feb 8.

Abstract

SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated protein kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. SHP2 also participates in the programed cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of SHP2 has been widely investigated, including in our previous reports describing SHP099 (2), which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies, reported here in the first of two papers, led to the identification of multiple 5,6-fused bicyclic scaffolds that bind to the same allosteric tunnel as 2. We demonstrate the structural diversity permitted by the tunnel pharmacophore and culminated in the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that modulate MAPK signaling in vivo. These studies also served as the basis for further scaffold morphing and optimization, detailed in the following manuscript.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Animals
  • Cell Line, Tumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / metabolism
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice, Inbred C57BL
  • Microsomes, Liver / metabolism
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Binding
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / chemistry
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Pyrazoles / chemical synthesis
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology*
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / metabolism
  • Pyrimidinones / pharmacology*
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Heterocyclic Compounds, 2-Ring
  • Pyrazoles
  • Pyrimidinones
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11