title: A DNA/HDAC dual-targeting drug CY190602 with significantly enhanced anticancer potency.
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 opportunity for improving cancer therapy.
authors.affiliation: Key Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Liu
authors.affiliation: Key Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Ding
authors.affiliation: Key Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Li
authors.affiliation: Clinic for Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Pallasch
authors.affiliation: Hangzhou Minsheng Pharma Research Institute Ltd, Hangzhou, China.
authors.forename: Liya
authors.initials: L
authors.lastname: Hong
authors.affiliation: Hangzhou Minsheng Pharma Research Institute Ltd, Hangzhou, China.
authors.forename: Dianwu
authors.initials: D
authors.lastname: Guo
authors.affiliation: Crystal Biopharmaceutical LLC, Pleasanton, CA, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Difei
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of New Mexico, Albuquerque, NM, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai, China yajiewa0459@163.com hemann@mit.edu hai@sibcb.ac.cn.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA yajiewa0459@163.com hemann@mit.edu hai@sibcb.ac.cn.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hemann
authors.affiliation: Key Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China yajiewa0459@163.com hemann@mit.edu hai@sibcb.ac.cn.
authors.forename: Hai
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D016503:Drug Delivery Systems; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D056572:Histone Deacetylase Inhibitors
keywords: DNA repair; HDAC; dual‐targeting anticancer drug; nitrogen mustard