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


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??M 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??M 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.

SUBMITTER: Zhang FC 

PROVIDER: S-EPMC7468272 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Zhang Feng-Cai FC   Sun Zhong-Ya ZY   Liao Li-Ping LP   Zuo Yu Y   Zhang Dan D   Wang Jun J   Chen Yan-Tao YT   Xiao Sen-Hao SH   Jiang Hao H   Lu Tian T   Xu Pan P   Yue Li-Yan LY   Du Dao-Hai DH   Zhang Hao H   Liu Chuan-Peng CP   Luo Cheng C  

Acta pharmacologica Sinica 20190628 2


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 inhi  ...[more]

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