Structure-based optimization of click-based histone deacetylase inhibitors

Jingli Hou; Congran Feng; Zhonghua Li; Qinghong Fang; Huihui Wang; Guoxian Gu; Yikang Shi; Pi Liu; Feng Xu; Zheng Yin; Jie Shen; Peng Wang

doi:10.1016/j.ejmech.2011.04.027

Structure-based optimization of click-based histone deacetylase inhibitors

Eur J Med Chem. 2011 Aug;46(8):3190-200. doi: 10.1016/j.ejmech.2011.04.027. Epub 2011 Apr 29.

Authors

Jingli Hou¹, Congran Feng, Zhonghua Li, Qinghong Fang, Huihui Wang, Guoxian Gu, Yikang Shi, Pi Liu, Feng Xu, Zheng Yin, Jie Shen, Peng Wang

Affiliation

¹ College of Pharmacy, Nankai University, 94 weijin Road, Nankai District, Tianjin 300071, China.

PMID: 21621883
DOI: 10.1016/j.ejmech.2011.04.027

Abstract

Previously, we reported a click-chemistry based approach to the synthesis of a novel class of histone deacetylase (HDAC) inhibitors [1]. The lead compound NSC746457 was found to be as potent as SAHA (Vorinostat). Further optimization of NSC746457 by using the HDAC2-TSA crystal structure is described herein. Docking of NSC746457 into HDAC2 binding domain suggested that the hydrophobic residue Phe210 flanking the cap-group binding-motif could be exploited for structural optimization. Substitution on the methylene group of cinnamic cap region led to identification of more potent HDAC inhibitors: isopropyl derivative 5 and tert-butyl derivative 6, with an IC(50) value of 22 nM and 18 nM, respectively.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects*
Click Chemistry
Crystallography, X-Ray
Drug Design
Drug Screening Assays, Antitumor
Histone Deacetylase 1 / chemistry*
Histone Deacetylase 1 / metabolism
Histone Deacetylase 2* / chemistry
Histone Deacetylase 2* / metabolism
Histone Deacetylase Inhibitors / chemical synthesis*
Histone Deacetylase Inhibitors / pharmacology
Humans
Hydrophobic and Hydrophilic Interactions
Hydroxamic Acids / chemical synthesis*
Hydroxamic Acids / pharmacology
Models, Molecular
Neoplasms / drug therapy
Neoplasms / enzymology*
Neoplasms / pathology
Phenylalanine / chemistry
Phenylalanine / metabolism
Protein Binding
Protein Structure, Secondary
Structure-Activity Relationship
Triazoles / chemical synthesis*
Triazoles / pharmacology
Vorinostat

Substances

3-(1-cinnamyl-1H-1,2,3-triazol-4-yl)-N-hydroxyacrylamide
Antineoplastic Agents
Histone Deacetylase Inhibitors
Hydroxamic Acids
Triazoles
Phenylalanine
Vorinostat
HDAC1 protein, human
HDAC2 protein, human
Histone Deacetylase 1
Histone Deacetylase 2