Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 55, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2021.116592
Keywords
BRD4 inhibitors; Virtual screening; Anticancer; Pharmacophore
Funding
- Postgraduate Research & Practice Innovation Program of Jiangsu Province [KYCX18_0771]
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This study designed a new series of 3-methyl-1H-indazole derivatives targeting the inhibitory activities of protein BRD4-BD1 and cancer cell proliferation. Compound 9d showed excellent selectivity for BRD4 and effectively suppressed c-Myc. The study provided new lead compounds for further evaluation on BRD4.
Bromodomain-containing Protein 4 (BRD4), an 'epigenetic reader', regulates chromatin structure and gene expression via recognizing and binding acetylated lysine in histones. BRD4 has become a therapeutic target for cancers because it promotes the expression of the tumor genes, such as c-Myc, NF-kappa B, and Bcl-2. In this study, a new series of 3-methyl-1H-indazole derivatives were designed via virtual screening and structure-based optimization. All compounds were synthesized and evaluated for their inhibitory activities to BRD4-BD1 and their antiproliferative effects in cancer cell lines. Among them, several compounds (such as 9d, 9u and 9w) exhibited strong BRD4-BD1 affinities and inhibition activities, and potently suppressed MV4;11 cancer cell line proliferation. Among them, compound 9d showed excellent selectivity for BRD4 and effectively suppressed c-Myc, the downstream protein of BRD4. This study provided new lead compounds for further biological evaluation on BRD4.
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