CUR - The Council on Undergraduate Research

Developing the Perfect Fit: Design, Synthesis and Evaluation of Histone Deacetylase Inhibitors for Anti-cancer, Neurological and Autoimmune Therapies

Ayanna Kemp, Arrington Moses, Kelsey Glasper, Kennedi Fitts, Brandon James, Liam Goldman, Xavier A. May, and Shana V. Stoddard, Chemistry Department, Rhodes College, 2000 North Parkway, 38112

Histone deacetylases (HDACs) are a family of 18 isozymes which have been shown to be excellent targets for anti-cancer, Huntington’s, and potentially autoimmune disease. Design of optimization rules which facilitate development of compounds that are potent binders to HDACs are important to further drug development. In this work compounds targeting the four of the isozymes HDAC2, HDAC8, HDAC4, and HDAC11, which implications for colorectal cancer, neuroblastoma, Huntington’s and glioblastoma, and multiple sclerosis respectively, have been developed. Compound datasets were designed to explore the binding preferences of the four HDAC receptors. Using molecular docking the binding pose of each compound was determined. Comparisons of the binding affinity and the structural differences exposed several structural features that facilitate strong binding the HDAC receptors. Evaluation of structural differences between the actives sites of HDAC2, HDAC8, HDAC4, and HDAC11 will be discussed in regards to implications for drug design and optimization of compounds targeting HDAC2, HDAC8, HDAC4, and HDAC11. The biological evaluation of the compounds developed for HDAC8 will also be presented. The structural considerations for design of HDAC inhibitors discovered in this work will be helpful for other scientist as they attempt to develop anti-cancer, neurological and autoimmune therapies that target members of the HDAC family.

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