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Discovery, Structure–Activity Relationship, and Biological Activity of Histone-Competitive Inhibitors of Histone Acetyltransferases P300/CBP

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posted on 21.04.2020, 14:51 by Fangrui Wu, Yuanda Hua, Salma Kaochar, Shenyou Nie, Yi-Lun Lin, Yuan Yao, Jingyu Wu, Xiaowei Wu, Xiaoyong Fu, Rachel Schiff, Christel M. Davis, Matthew Robertson, Erik A. Ehli, Cristian Coarfa, Nicholas Mitsiades, Yongcheng Song
Histone acetyltransferase (HAT) p300 and its paralog CBP acetylate histone lysine side chains and play critical roles in regulating gene transcription. The HAT domain of p300/CBP is a potential drug target for cancer. Through compound screening and medicinal chemistry, novel inhibitors of p300/CBP HAT with their IC50 values as low as 620 nM were discovered. The most potent inhibitor is competitive against histone substrates and exhibits a high selectivity for p300/CBP. It inhibited cellular acetylation and had strong activity with EC50 of 1–3 μM against proliferation of several tumor cell lines. Gene expression profiling in estrogen receptor (ER)-positive breast cancer MCF-7 cells showed that inhibitor treatment recapitulated siRNA-mediated p300 knockdown, inhibited ER-mediated gene transcription, and suppressed expression of numerous cancer-related gene signatures. These results demonstrate that the inhibitor is not only a useful probe for biological studies of p300/CBP HAT but also a pharmacological lead for further drug development targeting cancer.

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