A DNA/HDAC dual-targeting drug CY190602 with significantly enhanced anticancer potency

EMBO Molecular Medicine
Chuan LiuHai Jiang

Abstract

Genotoxic drugs constitute a major treatment modality for human cancers; however, cancer cells' intrinsic DNA repair capability often increases the threshold of lethality and renders these drugs ineffective. The emerging roles of HDACs in DNA repair provide new opportunities for improving traditional genotoxic drugs. Here, we report the development and characterization of CY190602, a novel bendamustine-derived drug with significantly enhanced anticancer potency. We show that CY190602's enhanced potency can be attributed to its newly gained ability to inhibit HDACs. Using this novel DNA/HDAC dual-targeting drug as a tool, we further explored HDAC's role in DNA repair. We found that HDAC activities are essential for the expression of several genes involved in DNA synthesis and repair, including TYMS, Tip60, CBP, EP300, and MSL1. Importantly, CY190602, the first-in-class example of such DNA/HDAC dual-targeting drugs, exhibited significantly enhanced anticancer activity in vitro and in vivo. These findings provide rationales for incorporating HDAC inhibitory moieties into genotoxic drugs, so as to overcome the repair capacity of cancer cells. Systematic development of similar DNA/HDAC dual-targeting drugs may represent a novel oppo...Continue Reading

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Feb 19, 2016·ChemMedChem·A Ganesan
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Nov 5, 2020·European Journal of Medicinal Chemistry·Gargi Nikhil VaidyaDinesh Kumar
Apr 23, 2020·Journal of Medicinal Chemistry·Tingting LiuGuiyun Duan

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Methods Mentioned

BETA
X-ray
histone acetylation
xenograft
acetylation
density gradient purification
flow cytometry

Software Mentioned

Prism
GraphPad Prism

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