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

Jiyong      Wu; Dongbo      Wang; Jing      Nie; Di      Zhang; Lei      Sun; Shifeng      Kan; Wei      Xu

doi:10.2174/1570180819666220530145951

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.

Keywords: Hsp90, histone deacetylase, multitarget, inhibitor, antitumor，docking simulation.

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Letters in Drug Design & Discovery

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

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Letters in Drug Design & Discovery

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

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