Design and Synthesis of an Hsp90 and HDAC Dual Inhibitor as Antitumor Agent

Author:

Xu Wei1,Wu Jiyong2,Wang Dongbo2,Nie Jing2,Zhang Di2,Sun Lei2,Kan Shifeng1

Affiliation:

1. Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250022, PR China

2. Department of Pharmacy, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250022, PR China

Abstract

Background: Cancer incidence and mortality have been increasing, and cancer is still the leading cause of death all over the world. Therefore, expanding the arsenal of anticancer drugs with high efficiency and low toxicity is still one of the most challenging tasks. As a branch of antitumor drug design and discovery, dual-targeting drug candidates draw extensive attention. Objective:: In this work, we try to construct a multitarget drug candidate and evaluate its antitumor effects. Methods: Hsp90 and histone deacetylase were selected as two targets to design a dual targeting inhibitor w11. Enzyme inhibition work, cell viability assay, and docking simulation were carried out to evaluate the activity of the compound. Results: w11 could inhibit the activity of Hsp90α and HDAC6 with the IC50 of 50.1 nM and 8.1 nM, respectively. In cell viability assay, five human tumor cell lines Eca-109, FaDu, HN6, MCF-7 and MDAMB- 231 were used, results showed that w11 could potently inhibit the proliferation of three human lines with IC50 values in the nM range. Molecular docking experiments proved the rationality of structure design. Conclusion: Compound w11 was a potent Hsp90 and HDAC dual inhibitor for anticancer research.

Publisher

Bentham Science Publishers Ltd.

Subject

Drug Discovery,Pharmaceutical Science,Molecular Medicine

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