Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor

J Med Chem. 2016 Sep 8;59(17):7773-82. doi: 10.1021/acs.jmedchem.6b00680. Epub 2016 Jul 12.

Abstract

SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.

Publication types

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

MeSH terms

  • Administration, Oral
  • Allosteric Regulation
  • Allosteric Site
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Design
  • Female
  • Heterografts
  • High-Throughput Screening Assays
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Nude
  • Models, Molecular
  • Neoplasm Transplantation
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology
  • Protein Conformation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / chemistry
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry*
  • Pyrazines / pharmacokinetics
  • Pyrazines / pharmacology
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Piperidines
  • Pyrazines
  • Pyrimidines
  • SHP099
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11