SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding

Bioorg Med Chem Lett. 2017 Apr 1;27(7):1576-1583. doi: 10.1016/j.bmcl.2017.02.030. Epub 2017 Feb 20.

Abstract

Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed.

Keywords: Cancer; EED; PRC2; Protein-protein interaction inhibitor (PPI).

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Humans
  • Ligands
  • Mice
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Polycomb Repressive Complex 2 / antagonists & inhibitors*
  • Polycomb Repressive Complex 2 / chemistry
  • Polycomb Repressive Complex 2 / metabolism*
  • Protein Binding
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • 1-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-4-(4-(4-(methanesulfonyl)piperazin-1-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine
  • Antineoplastic Agents
  • EED protein, human
  • Ligands
  • Pyrrolidines
  • Sulfonamides
  • Polycomb Repressive Complex 2