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 improv...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2015-03-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201404580 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849225972499349504 |
|---|---|
| author | Chuan Liu Hongyu Ding Xiaoxi Li Christian P Pallasch Liya Hong Dianwu Guo Yi Chen Difei Wang Wei Wang Yajie Wang Michael T Hemann Hai Jiang |
| author_facet | Chuan Liu Hongyu Ding Xiaoxi Li Christian P Pallasch Liya Hong Dianwu Guo Yi Chen Difei Wang Wei Wang Yajie Wang Michael T Hemann Hai Jiang |
| author_sort | Chuan Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-30e76dfa059a43f6964843534d03e6e7 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-30e76dfa059a43f6964843534d03e6e72025-08-24T11:44:26ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-03-017443844910.15252/emmm.201404580A DNA/HDAC dual‐targeting drug CY190602 with significantly enhanced anticancer potencyChuan Liu0Hongyu Ding1Xiaoxi Li2Christian P Pallasch3Liya Hong4Dianwu Guo5Yi Chen6Difei Wang7Wei Wang8Yajie Wang9Michael T Hemann10Hai Jiang11Key Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of SciencesKey Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of SciencesKey Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of SciencesClinic for Internal Medicine, University Hospital of CologneHangzhou Minsheng Pharma Research Institute LtdHangzhou Minsheng Pharma Research Institute LtdCrystal Biopharmaceutical LLCDepartment of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical CenterDepartment of Chemistry, University of New MexicoDepartment of Oncology, Changhai Hospital, Second Military Medical UniversityThe Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of TechnologyKey Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of SciencesAbstract 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.https://doi.org/10.15252/emmm.201404580DNA repairdual‐targeting anticancer drugHDACnitrogen mustard |
| spellingShingle | Chuan Liu Hongyu Ding Xiaoxi Li Christian P Pallasch Liya Hong Dianwu Guo Yi Chen Difei Wang Wei Wang Yajie Wang Michael T Hemann Hai Jiang A DNA/HDAC dual‐targeting drug CY190602 with significantly enhanced anticancer potency EMBO Molecular Medicine DNA repair dual‐targeting anticancer drug HDAC nitrogen mustard |
| title | A DNA/HDAC dual‐targeting drug CY190602 with significantly enhanced anticancer potency |
| title_full | A DNA/HDAC dual‐targeting drug CY190602 with significantly enhanced anticancer potency |
| title_fullStr | A DNA/HDAC dual‐targeting drug CY190602 with significantly enhanced anticancer potency |
| title_full_unstemmed | A DNA/HDAC dual‐targeting drug CY190602 with significantly enhanced anticancer potency |
| title_short | A DNA/HDAC dual‐targeting drug CY190602 with significantly enhanced anticancer potency |
| title_sort | dna hdac dual targeting drug cy190602 with significantly enhanced anticancer potency |
| topic | DNA repair dual‐targeting anticancer drug HDAC nitrogen mustard |
| url | https://doi.org/10.15252/emmm.201404580 |
| work_keys_str_mv | AT chuanliu adnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT hongyuding adnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT xiaoxili adnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT christianppallasch adnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT liyahong adnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT dianwuguo adnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT yichen adnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT difeiwang adnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT weiwang adnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT yajiewang adnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT michaelthemann adnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT haijiang adnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT chuanliu dnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT hongyuding dnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT xiaoxili dnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT christianppallasch dnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT liyahong dnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT dianwuguo dnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT yichen dnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT difeiwang dnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT weiwang dnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT yajiewang dnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT michaelthemann dnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency AT haijiang dnahdacdualtargetingdrugcy190602withsignificantlyenhancedanticancerpotency |