Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma.
J Enzyme Inhib Med Chem
; 34(1): 1062-1077, 2019 Dec.
Article
en En
| MEDLINE
| ID: mdl-31072216
ABSTRACT
Histone deacetylase 6 (HDAC6) is an attractive target for cancer therapeutic intervention. Selective HDAC6 inhibitors is important to minimise the side effects of pan inhibition. Thus, new class of hydroxamic acid-based derivatives were designed on structural basis to perform preferential activity against HDAC6 targeting solid tumours. Interestingly, 1-benzylbenzimidazole-2-thio-N-hydroxybutanamide 10a showed impressive preference with submicromolar potency against HDAC6 (IC50 = 510 nM). 10a showed cytotoxic activity with interesting profile against CCHE-45 at (IC50 = 112.76 µM) when compared to standard inhibitor Tubacin (IC50 = 20 µM). Western blot analysis of acetylated-α-tubulin verified the HDAC6 inhibiting activity of 10a. Moreover, the insignificant difference in acetylated-α-tubulin induced by 10a and Tubacin implied the on-target cytotoxic activity of 10a. Docking of 10a in the binding site of HDAC6 attributed the activity of 10a to π-π stacking with the amino acids of the hydrophobic channel of HDAC6 and capture of zinc metal in bidentate fashion. The therapeutic usefulness besides the on-target activity may define 10a as an interesting safe-lead inhibitor for future development.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Carcinoma
/
Diseño de Fármacos
/
Neoplasias del Plexo Coroideo
/
Inhibidores de Histona Desacetilasas
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Histona Desacetilasa 6
/
Ácidos Hidroxámicos
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
J Enzyme Inhib Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Egipto