2. Academic Validation
  3. Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities

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

  • J Med Chem. 2015 Oct 8;58(19):7672-80. doi: 10.1021/acs.jmedchem.5b01044.
Yiwu Yao 1,  Zhengchao Tu 1,  Chenzhong Liao 2,  Zhen Wang 1,  Shang Li 1,  Hequan Yao 3,  Zheng Li 4,  Sheng Jiang 1
Affiliations

Affiliations

  • 1 Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 2 School of Medical Engineering, Hefei University of Technology , Hefei, Anhui 230009, China.
  • 3 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University , Nanjing, 210009, China.
  • 4 Department of Nanomedicine, Houston Methodist Hospital Research Institute , Houston, Texas 77030, United States.
PMID: 26331334 DOI: 10.1021/acs.jmedchem.5b01044
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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