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Discovery of novel CBP bromodomain inhibitors through TR-FRET-based high-throughput screening

  
@article{APS10098,
	author = {Feng-cai Zhang and Zhong-ya Sun and Li-ping Liao and Yu Zuo and Dan Zhang and Jun Wang and Yan-tao Chen and Sen-hao Xiao and Hao Jiang and Tian Lu and Pan Xu and Li-yan Yue and Dao-hai Du and Hao Zhang and Chuan-peng Liu and Cheng Luo},
	title = {Discovery of novel CBP bromodomain inhibitors through TR-FRET-based high-throughput screening},
	journal = {Acta Pharmacologica Sinica},
	volume = {41},
	number = {2},
	year = {2020},
	keywords = {},
	abstract = {The cAMP-responsive element binding protein (CREB) binding protein (CBP) and adenoviral E1A-binding protein (P300) are two closely related multifunctional transcriptional coactivators. Both proteins contain a bromodomain (BrD) adjacent to the histone acetyl transferase (HAT) catalytic domain, which serves as a promising drug target for cancers and immune system disorders. Several potent and selective small-molecule inhibitors targeting CBP BrD have been reported, but thus far small-molecule inhibitors targeting BrD outside of the BrD and extraterminal domain (BET) family are especially lacking. Here, we established and optimized a TR-FRET-based high-throughput screening platform for the CBP BrD and acetylated H4 peptide. Through an HTS assay against an in-house chemical library containing 20 000 compounds, compound DC_CP20 was discovered as a novel CBP BrD inhibitor with an IC50 value of 744.3 nM. This compound bound to CBP BrD with a KD value of 4.01 μM in the surface plasmon resonance assay. Molecular modeling revealed that DC_CP20 occupied the Kac-binding region firmly through hydrogen bonding with the conserved residue N1168. At the celluslar level, DC_CP20 dose-dependently inhibited the proliferation of human leukemia MV4-11 cells with an IC50 value of 19.2 μM and markedly downregulated the expression of the c-Myc in the cells. Taken together, the discovery of CBP BrD inhibitor DC_CP20 provides a novel chemical scaffold for further medicinal chemistry optimization and a potential chemical probe for CBP-related biological function research. In addition, this inhibitor may serve as a promising therapeutic strategy for MLL leukemia by targeting CBP BrD protein.},
	url = {http://www.chinaphar.com/article/view/10098}
}