Universität zu Köln

Liu, Chuan, Ding, Hongyu ORCID: 0000-0002-7531-4771, Li, Xiaoxi, Pallasch, Christian P. ORCID: 0000-0001-5675-6905, Hong, Liya, Guo, Dianwu, Chen, Yi, Wang, Difei, Wang, Wei, Wang, Yajie, Hemann, Michael T. and Jiang, Hai (2015). A DNA/HDAC dual-targeting drug CY190602 with significantly enhanced anticancer potency. EMBO Mol. Med., 7 (4). S. 438 - 450. HOBOKEN: WILEY. ISSN 1757-4684

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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 invitro and invivo. 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Liu, Chuan UNSPECIFIED UNSPECIFIED UNSPECIFIED Ding, Hongyu UNSPECIFIED orcid.org/0000-0002-7531-4771 UNSPECIFIED Li, Xiaoxi UNSPECIFIED UNSPECIFIED UNSPECIFIED Pallasch, Christian P. UNSPECIFIED orcid.org/0000-0001-5675-6905 UNSPECIFIED Hong, Liya UNSPECIFIED UNSPECIFIED UNSPECIFIED Guo, Dianwu UNSPECIFIED UNSPECIFIED UNSPECIFIED Chen, Yi UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Difei UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Wei UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Yajie UNSPECIFIED UNSPECIFIED UNSPECIFIED Hemann, Michael T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jiang, Hai UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-403366
DOI:	10.15252/emmm.201404580
Journal or Publication Title:	EMBO Mol. Med.
Volume:	7
Number:	4
Page Range:	S. 438 - 450
Date:	2015
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1757-4684
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-DAMAGE RESPONSE; FANCONI-ANEMIA; REPAIR PATHWAYS; BENDAMUSTINE; KINASE; ACETYLATION; INHIBITORS; LINK; ATM; PHOSPHORYLATION Multiple languages Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40336