Structure-Activity Relationships and Kinetic Studies of Peptidic Antagonists of CBX Chromodomains

J Med Chem. 2016 Oct 13;59(19):8913-8923. doi: 10.1021/acs.jmedchem.6b00801. Epub 2016 Sep 19.


To better understand the contribution of methyl-lysine (Kme) binding proteins to various disease states, we recently developed and reported the discovery of 1 (UNC3866), a chemical probe that targets two families of Kme binding proteins, CBX and CDY chromodomains, with selectivity for CBX4 and -7. The discovery of 1 was enabled in part by the use of molecular dynamics simulations performed with CBX7 and its endogenous substrate. Herein, we describe the design, synthesis, and structure-activity relationship studies that led to the development of 1 and provide support for our model of CBX7-ligand recognition by examining the binding kinetics of our antagonists with CBX7 as determined by surface-plasmon resonance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Kinetics
  • Models, Molecular
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacology*
  • Polycomb Repressive Complex 1 / antagonists & inhibitors*
  • Polycomb Repressive Complex 1 / chemistry
  • Polycomb Repressive Complex 1 / metabolism*
  • Structure-Activity Relationship
  • Surface Plasmon Resonance


  • CBX7 protein, human
  • Oligopeptides
  • UNC3866
  • Polycomb Repressive Complex 1