Drug Discovery and Drug Design

Biography

Biography: Kunal Nepali

Abstract

Histone deacetylase 6 (HDAC6) has been recognized as a promising target for tumorigenesis. A selective HDAC6 inhibitor, Tubastatin posseses tetrahydrocarbolines as the CAP construct and has been a subject of extensive structural engineering. Several alterations have been made in its chemical architecture to furnish selective HDAC 6 inhibitors inducing potent antiproliferative effects. Recently, a series of selective HDAC6 inhibitors were designed by our research group employing a ring opening strategy of tetrahydro-γ-carbolines in tubastatin A to generate diverse indole based constructs. The aim of the study was to evaluate the influence of diverse combinations of CAP constructs and linkers bearing the N1-zinc binding domain on the cellular and enzymatic activity. The synthesized compounds were evaluated for in-vitro antiproliferative effects against a panel of human cancer cell lines. The results of the study revealed interesting insights regarding the dependence of activity profile of the compounds on the subtle structural variations. It was found that some selected compounds displayed selective HDAC6 activity comparable to that of tubastatin A. Moroever, significant cell killing effects against HCT116 cells with GI₅₀ ranging from 0.50 – 0.54 µM were also demonstrated by some compounds. The synthetics activated the apoptosis pathway and induced irreversible growth arrest capacities by suppressing colony formation ability. To add on, an upregulation effect on acetyl-tubulin, without significant induction of acetyl-histone H3 was observed by western blot analysis. Overall, the findings of the study are highly promising and the potent compounds identified could emerge as a potential leads for further investigation to develop potent anticancer agents for colon cancer.