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bioRxiv · 10.1101/2024.05.03.592353

Paralogue-selective degradation of the lysine acetyltransferase EP300

Chen, X.·Crawford, M. C.·Xiong, Y.·Shaik, A. B.·Suazo, K. F.·Penikalapati, M. S.·Williams, J. H.·Andresson, T.·Swenson, R. E.·Meier, J. L.
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Abstract

The transcriptional coactivators EP300 and CREBBP are critical regulators of gene expression that share high sequence identity but exhibit non-redundant 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 non-catalytic 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.

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Chen, X., Crawford, M. C., Xiong, Y., Shaik, A. B., Suazo, K. F., Penikalapati, M. S., Williams, J. H., Andresson, T., Swenson, R. E., Meier, J. L.. 2024-05-05. Paralogue-selective degradation of the lysine acetyltransferase EP300. https://doi.org/10.1101/2024.05.03.592353

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