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

作　　者：Feng-cai Zhang Zhong-ya Sun Li-ping Liao Yu Zuo Dan Zhang Jun Wang Yan-tao Chen Sen-hao Xiao Hao Jiang Tian Lu Pan Xu Li-yan Yue Dao-hai Du Hao Zhang Chuan-peng Liu Cheng Luo 

机构地区：[1]School of Pharmacy,Nanchang University,Nanchang 330006,China [2]School of Life and Technology,Harbin Institute of Technology,Harbin 150001,China [3]Drug Discovery and Design Center,CAS Key Laboratory of Receptor Research,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [4]University of Chinese Academy of Sciences,Beijing 100049,China [5]Department of Pharmacy,Guizhou University of Traditional Chinese Medicine,Guiyang 550025,China [6]Jiangsu Key Laboratory for High Technology Research of TCM Formulae,Nanjing University of Chinese Medicine,Nanjing 210023,China

出　　处：《Acta Pharmacologica Sinica》2020年第2期286-292,共7页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(91853205 and 81625022 to CL,81430084 to DHD);KC Wong Education Foundation to CL,Chinese Academy of Sciences(XDA12020353 to CL and CASIMM0120184015 to HZ);China Postdoctoral Science Foundation(2017M621571 to LYY);Science and Technology Commission of Shanghai Municipality(18431907100 and 19XD1404700 to CL);National Science&Technology Major Project of China(2018ZX09711002 to DHD).

摘　　要：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 20000 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 4.01μM 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 19.2μM 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.

关 键 词：CBP BROMODOMAIN SMALL-MOLECULE inhibitor HIGH-THROUGHPUT screening TR-FRET molecular modeling human LEUKEMIA MV4-11 cells 

分 类 号：R965[医药卫生—药理学]