Abstract
In our quest to understand why dimethyl sulfoxide (DMSO) can cause growth arrest and terminal differentiation of transformed cells, we followed a path that led us to discover suberoylanilide hydroxamic acid (SAHA; vorinostat (Zolinza)), which is a histone deacetylase inhibitor. SAHA reacts with and blocks the catalytic site of these enzymes. Extensive structure-activity studies were done along the path from DMSO to SAHA. SAHA can cause growth arrest and death of a broad variety of transformed cells both in vitro and in tumor-bearing animals at concentrations not toxic to normal cells. SAHA has many protein targets whose structure and function are altered by acetylation, including chromatin-associated histones, nonhistone gene transcription factors and proteins involved in regulation of cell proliferation, migration and death. In clinical trials, SAHA has shown significant anticancer activity against both hematologic and solid tumors at doses well tolerated by patients. A new drug application was approved by the US Food and Drug Administration for vorinostat for treatment of cutaneous T-cell lymphoma. More potent analogs of SAHA have shown unacceptable toxicity.
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Acknowledgements
The studies reviewed in this paper have been supported over the past 30 or more years by grants from the US National Institutes of Health, US National Science Foundation, Susan and Jack Rudin Foundation, David H. Koch Prostate Cancer Research Award, Robert J. and Helen C. Kleberg Foundation, DeWitt Wallace Fund for the MSKCC and the Japan Foundation for the Promotion of Cancer Research.
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Memorial Sloan-Kettering Cancer Center and Columbia University jointly hold patents on hydroxamic-based polar compounds, including SAHA, that were exclusively licensed to Aton Pharma Inc., a biotech company acquired by Merck, Inc. in April 2004. P.A.M. and R.B. were among the founders of Aton and have a financial interest in Merck’s further development of SAHA.
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Marks, P., Breslow, R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol 25, 84–90 (2007). https://doi.org/10.1038/nbt1272
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DOI: https://doi.org/10.1038/nbt1272
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