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

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journal contribution
posted on 29.08.2016, 00:00 by Jacob I. Stuckey, Catherine Simpson, Jacqueline L. Norris-Drouin, Stephanie H. Cholensky, Junghyun Lee, Ryan Pasca, Nancy Cheng, Bradley M. Dickson, Kenneth H. Pearce, Stephen V. Frye, Lindsey I. James
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.