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.