Open AccessStructural and in Vivo Characterization of Tubastatin A, a Widely Used Histone Deacetylase 6 Inhibitor
Author(s) -
Sida Shen,
Michal Svoboda,
Guangming Zhang,
Maria A. Cavasin,
L. Motlova,
Timothy A. McKinsey,
James H. Eubanks,
Cyril Bařinka,
Alan P. Kozikowski
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00560
Subject(s) - hdac6 , in vivo , acetylation , histone deacetylase inhibitor , histone deacetylase , in vitro , pharmacology , chemistry , histone , computational biology , medicine , biochemistry , biology , gene , genetics
Tubastatin A, a tetrahydro-γ-carboline-capped selective HDAC6 inhibitor (HDAC6i), was rationally designed 10 years ago, and has become the best investigated HDAC6i to date. It shows efficacy in various neurological disease animal models, as HDAC6 plays a crucial regulatory role in axonal transport deficits, protein aggregation, as well as oxidative stress. In this work, we provide new insights into this HDAC6i by investigating the molecular basis of its interactions with HDAC6 through X-ray crystallography, determining its functional capability to elevate the levels of acetylated α-tubulin in vitro and in vivo, correlating PK/PD profiles to determine effective doses in plasma and brain, and finally assessing its therapeutic potential toward psychiatric diseases through use of the SmartCube screening platform.