Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A.
Structure-based drug design combined with homology modeling techniques were used to develop potent inhibitors of HDAC6 that display superior selectivity for the HDAC6 isozyme compared to other inhibitors. These inhibitors can be assembled in a few synthetic steps, and thus are readily scaled up for in vivo studies. An optimized compound from this series, designated Tubastatin A, was tested in primary cortical neuron cultures in which it was found to induce elevated levels of acetylated alpha-tubulin, but not histone, consistent with its HDAC6 selectivity. Tubastatin A also conferred dose-dependent protection in primary cortical neuron cultures against glutathione depletion-induced oxidative stress. Importantly, when given alone at all concentrations tested, this hydroxamate-containing HDAC6-selective compound displayed no neuronal toxicity, thus, forecasting the potential application of this agent and its analogues to neurodegenerative conditions.
Butler
Kyle V
KV
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood, Chicago, Illinois 60612, USA.
Kalin
Jay
J
Brochier
Camille
C
Vistoli
Guilio
G
Langley
Brett
B
Kozikowski
Alan P
AP
D000813:Anilides / Q000737:chemistry / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006710:Homocysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000813:Anilides; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D007527:Isoenzymes; D018696:Neuroprotective Agents; C474316:tubacin; D006710:Homocysteine; C007956:homocysteic acid; C553587:tubastatin A; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases