A DNA/HDAC dual-targeting drug CY190602 with significantly enhanced anticancer potency
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 tradi...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Wiley Blackwell
2015
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| Online Access: | http://hdl.handle.net/1721.1/97593 |
| _version_ | 1811082784257605632 |
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| author | Hemann, Michael Liu, Chuan Ding, Hongyu Li, Xiaoxi Pallasch, Christian Hong, Liya Guo, Dianwu Chen, Yi Wang, Difei Wang, Wei Wang, Yajie Jiang, Hai, 1979- |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Hemann, Michael Liu, Chuan Ding, Hongyu Li, Xiaoxi Pallasch, Christian Hong, Liya Guo, Dianwu Chen, Yi Wang, Difei Wang, Wei Wang, Yajie Jiang, Hai, 1979- |
| author_sort | Hemann, Michael |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T12:08:56Z |
| format | Article |
| id | mit-1721.1/97593 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:08:56Z |
| publishDate | 2015 |
| publisher | Wiley Blackwell |
| record_format | dspace |
| spelling | mit-1721.1/975932022-09-28T00:29:21Z A DNA/HDAC dual-targeting drug CY190602 with significantly enhanced anticancer potency Hemann, Michael Liu, Chuan Ding, Hongyu Li, Xiaoxi Pallasch, Christian Hong, Liya Guo, Dianwu Chen, Yi Wang, Difei Wang, Wei Wang, Yajie Jiang, Hai, 1979- Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Hemann, Michael 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. National Institutes of Health (U.S.) (RO1 CA128803) Massachusetts Institute of Technology. Ludwig Center for Molecular Oncology 2015-06-30T18:06:47Z 2015-06-30T18:06:47Z 2015-03 2015-02 Article http://purl.org/eprint/type/JournalArticle 1757-4676 1757-4684 http://hdl.handle.net/1721.1/97593 Liu, C., H. Ding, X. Li, C. P. Pallasch, L. Hong, D. Guo, Y. Chen, et al. “A DNA/HDAC Dual-Targeting Drug CY190602 with Significantly Enhanced Anticancer Potency.” EMBO Molecular Medicine 7, no. 4 (March 9, 2015): 438–449. en_US http://dx.doi.org/10.15252/emmm.201404580 EMBO Molecular Medicine Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Wiley Blackwell Wiley Blackwell |
| spellingShingle | Hemann, Michael Liu, Chuan Ding, Hongyu Li, Xiaoxi Pallasch, Christian Hong, Liya Guo, Dianwu Chen, Yi Wang, Difei Wang, Wei Wang, Yajie Jiang, Hai, 1979- A DNA/HDAC dual-targeting drug CY190602 with significantly enhanced anticancer potency |
| 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 |
| url | http://hdl.handle.net/1721.1/97593 |
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