Characterization of Conformationally Constrained Benzanilide Scaffolds for Potent and Selective HDAC8 Targeting
| Autor: | Muhammad Murtaza Hassan, Yasir S. Raouf, Pimyupa Manaswiyoungkul, Aaron D. Cabral, Abootaleb Sedighi, Rabia Altintas, Fettah Erdogan, Patrick T. Gunning, Giovanni Ganda, David W.J. Armstrong, Olasunkanmi O. Olaoye, Elvin D. de Araujo, Johan Israelian, Fabrizio Angeles, Nabanita Nawar |
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| Rok vydání: | 2020 |
| Předmět: |
01 natural sciences
Histone Deacetylases 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Catalytic Domain Drug Discovery Humans Anilides IC50 030304 developmental biology chemistry.chemical_classification 0303 health sciences Gene knockdown biology Benzanilide HDAC8 Combinatorial chemistry In vitro 0104 chemical sciences 3. Good health Histone Deacetylase Inhibitors Molecular Docking Simulation Repressor Proteins 010404 medicinal & biomolecular chemistry Enzyme Histone chemistry Drug Design biology.protein Molecular Medicine Selectivity |
| Zdroj: | Journal of medicinal chemistry. 63(15) |
| ISSN: | 1520-4804 |
| Popis: | Histone deacetylases (HDACs) are an attractive therapeutic target for a variety of human diseases. Currently, all four FDA-approved HDAC-targeting drugs are nonselective, pan-HDAC inhibitors, exhibiting adverse side effects at therapeutic doses. Although selective HDAC inhibition has been proposed to mitigate toxicity, the targeted catalytic domains are highly conserved. Herein, we describe a series of rationally designed, conformationally constrained, benzanilide foldamers which selectively bind the catalytic tunnel of HDAC8. The series includes benzanilides, MMH371, MMH409, and MMH410, which exhibit potent in vitro HDAC8 activity (IC50 = 66, 23, and 66 nM, respectively) and up to 410-fold selectivity for HDAC8 over the next targeted HDAC. Experimental and computational analyses of the benzanilide structure docked with human HDAC8 enzyme showed the adoption of a low-energy L-shaped conformer that favors HDAC8 selectivity. The conformationally constrained HDAC8 inhibitors present an alternative biological probe for further determining the clinical utility and safety of pharmacological knockdown of HDAC8 in diseased cells. |
| Databáze: | OpenAIRE |
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