UNC3866 is a potent antagonist of CBX4 and CBX7 chromodomains with a Kd of ~100 nM for each, and is 6- to 18-fold selective as compared to seven other CBX and CDY chromodomains. UNC3866 antagonizes the methyllysine (Kme) reading function of the Polycomb CBX and CDY families of chromodomains. [1]
UNC3866 is the most potent ligand reported for CBX7, with a Kd of 97 ± 2.4 nM. UNC3866 antagonizes the CBX7-H3 interaction, assayed by AlphaScreen (IC50 = 66 ± 1.2 nM). Affinity of UNC3866 for CBX2, CBX4, CBX6 and CBX8 is surprisingly well associated with the percent sequence identity of each chromodomain relative to that of CBX7. UNC3866 is equally potent for CBX4, which is most similar to CBX7, whereas it is 18-, 6- and 12-fold selective for CBX4 and CBX7 over CBX2, CBX6 and CBX8, respectively. UNC3866 is 65-fold selective for CBX4 and CBX7 over CDY1 and 9-fold selective for CBX4 and CBX7 over CDYL1b and CDYL2. Each backbone amide of UNC3866 engages in at least one hydrogen bond with the backbone of CBX7, while the N-terminal tert-butylbenzoyl cap of UNC3866 primarily connects the side chains of D50, R52 and L53. X-ray crystallography exhibited that interactions of UNC3866 and the CBX chromodomains closely mock those of the methylated H3 tail. UNC3866 suppresses PC3 cell proliferation, consistent with the known ability of CBX7 overexpression to confer a growth advantage. [1]
Reference:
1.A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1. Nat Chem Biol. 2016 Mar;12(3):180-7.