Discovery and biological evaluation of thiobarbituric derivatives as potent p300/CBP inhibitors. Issue 20 (1st November 2018)

• Record Type: Journal Article
• Authors: Lu, Wenchao; Xiong, Huan; Chen, Yu; Wang, Chen; Zhang, Hao; Xu, Pan; Han, Jie; Xiao, Senhao; Ding, Hong; Chen, Zhifeng; Lu, Tian; Wang, Jun; Zhang, Yuanyuan; Yue, Liyan; Liu, Yu-Chih; Zhang, Chenhua; Yang, Yaxi; Jiang, Hualiang; Chen, Kaixian; Zhou, Bing; Luo, Cheng
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 20(2018)
• Page Start: 5397
• Page End: 5407
• Publication Date: 2018-11-01
• Subjects: Drug discovery -- Epigenetics -- Histone acetyltransferase -- P300/CBP; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.07.048
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: A potent p300/CBP inhibitor with a new scaffold was identified via virtual screening and chemical optimization. The inhibitory activity of DCH36_06 was demonstrated by radioisotope assays. DCH36_06 presented potent anti-proliferation as well as anti-tumor activity in leukemia xenograft. DCH36_06 could serve as the starting point to develop more potent HATs inhibitors. Abstract: Histone acetyltransferases (HATs) relieve transcriptional repression by preferentially acetylation of ε-amino group of lysine residues on histones. Dysregulation of HATs is strongly correlated with etiology of several diseases especially cancer, thus highlighting the utmost significance of the development of small molecule inhibitors against this potential therapeutic target. In the present study, through virtual screening and iterative optimization, we identified DCH36_06 as a bona fide, potent p300/CBP inhibitor. DCH36_06 mediated p300/CBP inhibition leading to hypoacetylation on H3K18 in leukemic cells. The suppression of p300/CBP activity retarded cell proliferation in several leukemic cell lines. In addition, DCH36_06 arrested cell cycle at G1 phase and induced apoptosis via activation of capase3, caspase9 and PARP that elucidated the molecular mechanism of its anti-proliferation activity. In transcriptome analysis, DCH36_06 altered downstream gene expression and apoptotic pathways-related genes verified by real-time PCR. Importantly, DCH36_06 blocked the leukemic xenograft growth in mice supporting its potential for in vivo use that underlies the therapeutic potential for p300/CBP inhibitors in clinical translation. Taken together, our findings suggest that DCH36_06 may serve as a qualified chemical tool to decode the acetylome code and open up new opportunities for clinical intervention.