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J Med Chem. 2016 Oct 13;59(19):8913-8923. Epub 2016 Sep 19.

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

Author information

1
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.

Abstract

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.

PMID:
27571219
PMCID:
PMC5063714
DOI:
10.1021/acs.jmedchem.6b00801
[Indexed for MEDLINE]
Free PMC Article

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