Fragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4728-4732. doi: 10.1016/j.bmcl.2015.08.048. Epub 2015 Aug 22.

Abstract

A fragment-based lead discovery approach was used to discover novel ERK2 inhibitors. The crystal structure of N-benzyl-9H-purin-6-amine 1 in complex with ERK2 elucidated its hinge-binding mode. In addition, the simultaneous binding of an imidazole molecule adjacent to 1 suggested a direction for fragment expansion. Structure-based core hopping applied to 1 led to 5H-pyrrolo[3,2-b]pyrazine (3) that afforded direct vectors to probe the pockets of interest while retaining the essential hinge binding elements. Utilizing the new vectors for SAR exploration, the new core 3 was quickly optimized to compound 39 resulting in a greater than 6600-fold improvement in potency.

Keywords: ERK2; Extracellular-regulated kinase; Fragment-based; Pyrrolopyrazine.

Publication types

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

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Models, Molecular
  • Molecular Structure
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry
  • Pyrazines / pharmacology*
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship

Substances

  • Pyrazines
  • Pyrroles
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1