Browsing by Author "Kassab, SE"

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    Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma
    (TAYLOR & FRANCIS LTD, 2019-01) Kassab, SE; Mowafy, S; Alserw, AM; Seliem, JA; El-Naggar, SM; Omar, NN; Awad, MM
    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 mu M) when compared to standard inhibitor Tubacin (IC50 = 20 mu M). Western blot analysis of acetylated-alpha-tubulin verified the HDAC6 inhibiting activity of 10a. Moreover, the insignificant difference in acetylated-alpha-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 pi-pi 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.