Abstract
Epigenetic regulation of gene expression without changing DNA sequences is a promising strategy in developing therapeutic agents for human diseases, especially cancer. Histone deacetylases (HDACs) are a family of enzymes involved in epigenetic modulation of gene expression by chromatin remodeling. Deacetylation of the lysine side chains of histones by HDAC proteins renders DNA transcriptionally inactive, resulting in the inhibition of expression of tumor suppressor genes, leading to tumorigenesis and tumor progression. Therefore, inhibiting HDAC enzymes has become an attractive strategy to modulate gene expression as a strategy for developing anticancer drugs. There are currently four FDA-approved cancer drugs in clinical use, and many more are in different stages of clinical trials. However, their clinical utility is limited due to undesirable side effects, mainly attributed to their lack of selectivity and the presence of a hydroxamic acid moiety as the metal-binding group. There are eighteen different isoforms of HDACs belonging to four classes that have been identified in humans. A major challenge in HDAC inhibitor development is how to make them selective for these HDAC isoforms and classes. We report the design and synthesis of new classes of HDAC inhibitors and the evaluation of their anticancer activity and selectivity.
Highlights
Viranga Tillekeratne 1,*, Ayad Ayad Al-Hamashi 1, Samkeliso Dlamini 1, William Taylor 2, Radhika Koranne 2, Mary Kay Pflum 3, Ahmed T
Drug Discovery, Barcelona, Spain, 15–17 May 2019. ‡ Current address: Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman 4184, UAE. § Current address: Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo
* Correspondence: ltillek@utnet.utoledo.edu † Presented at the 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in
Summary
Viranga Tillekeratne 1,*, Ayad Ayad Al-Hamashi 1, Samkeliso Dlamini 1, William Taylor 2, Radhika Koranne 2, Mary Kay Pflum 3, Ahmed T. Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43606, USA Department of Biological Sciences, College of Natural Sciences and Mathematics, University of Toledo, Toledo, OH 43606, USA
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