Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology

Bioorg Med Chem Lett. 2018 Jun 15;28(11):2029-2034. doi: 10.1016/j.bmcl.2018.04.063. Epub 2018 Apr 26.

Abstract

Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100 nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10 mpk = 0 μM h; F% = 0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10 mpk = 26 μM h; F% = 70).

Keywords: ATP competitive; ERK inhibitor; Kinase selectivity; MAP kinases; Oncology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • 3(S)-thiomethyl pyrrolidine
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrrolidines
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3