Open AccessA DNA / HDAC dual‐targeting drug CY 190602 with significantly enhanced anticancer potency
Author(s) -
Liu Chuan,
Ding Hongyu,
Li Xiaoxi,
Pallasch Christian P,
Hong Liya,
Guo Dianwu,
Chen Yi,
Wang Difei,
Wang Wei,
Wang Yajie,
Hemann Michael T,
Jiang Hai
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404580
Subject(s) - dna damage , dna repair , potency , drug , in vivo , histone deacetylase , synthetic lethality , pharmacology , dna , chemistry , cancer research , in vitro , biology , histone , biochemistry , genetics
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 HDAC s in DNA repair provide new opportunities for improving traditional genotoxic drugs. Here, we report the development and characterization of CY 190602, a novel bendamustine‐derived drug with significantly enhanced anticancer potency. We show that CY 190602's enhanced potency can be attributed to its newly gained ability to inhibit HDAC s. 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 , EP 300, and MSL 1. Importantly, CY 190602, 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 opportunity for improving cancer therapy.