Paralogue-Selective Degradation of the Lysine Acetyltransferase EP300

The transcriptional coactivators EP300 and CREBBP are
critical
regulators of gene expression that share high sequence identity but
exhibit nonredundant functions in basal and pathological contexts.
Here, we report the development of a bifunctional small molecule,
MC-1, capable of selectively degrading EP300 over CREBBP. Using a
potent aminopyridine-based inhibitor of the EP300/CREBBP catalytic
domain in combination with a VHL ligand, we demonstrate that MC-1
preferentially degrades EP300 in a proteasome-dependent manner. Mechanistic
studies reveal that selective degradation cannot be predicted solely
by target engagement or ternary complex formation, suggesting additional
factors govern paralogue-specific degradation. MC-1 inhibits cell
proliferation in a subset of cancer cell lines and provides a new
tool to investigate the noncatalytic functions of EP300 and CREBBP.
Our findings expand the repertoire of EP300/CREBBP-targeting chemical
probes and offer insights into the determinants of selective degradation
of highly homologous proteins.