Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities

Journal of Medicinal Chemistry
Yiwu YaoSheng Jiang

Abstract

A successful structure-based design of novel cyclic depsipeptides that selectively target class I HDAC isoforms is described. Compound 11 has an IC50 of 2.78 nM for binding to the HDAC1 protein, and the prodrugs 12 and 13 also exhibit promising antiproliferative activities in the nanomolar range against various cancer cell lines. Compounds 12 and 13 show more than 20-fold selectivity toward human cancer cells over human normal cells in comparison with romidepsin (FK228), demonstrating low probability of toxic side effects. In addition, compound 13 exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft model with no observed toxicity. Thus, prodrug 13 has therapeutic potential as a new class of anticancer agent for further clinical translation.

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Citations

Feb 10, 2017·Medicinal Research Reviews·Chiara ZagniAntonio Rescifina
Jan 20, 2017·Epigenomics·Chiara AngiolilliKris A Reedquist
Apr 11, 2018·Topics in Current Chemistry·Ming Wang, Xuefeng Jiang
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Nov 17, 2020·Heliyon·Nausheen JoondanSabina Jhaumeer Laulloo
Dec 4, 2019·ACS Omega·Zsófia KutilMike Schutkowski
May 2, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Sheng YangMei Dong

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