Isoform-Selective ATAD2 Chemical Probe with Novel Chemical Structure and Unusual Mode of Action.
Fernández-Montalván AE., Berger M., Kuropka B., Koo SJ., Badock V., Weiske J., Puetter V., Holton SJ., Stöckigt D., Ter Laak A., Centrella PA., Clark MA., Dumelin CE., Sigel EA., Soutter HH., Troast DM., Zhang Y., Cuozzo JW., Keefe AD., Roche D., Rodeschini V., Chaikuad A., Díaz-Sáez L., Bennett JM., Fedorov O., Huber KVM., Hübner J., Weinmann H., Hartung IV., Gorjánácz M.
ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.