Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma. (1st January 2019)

• Record Type: Journal Article
• Authors: Kassab, Shaymaa E.; Mowafy, Samar; Alserw, Aya M.; Seliem, Joustin A.; El-Naggar, Shahenda M.; Omar, Nesreen N.; Awad, Mohamed M.
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 34:Number 1(2019)
• Page Start: 1062
• Page End: 1077
• Publication Date: 2019-01-01
• Subjects: Preferential HDAC6 inhibitor -- acetylated-α-tubulin -- on-target activity -- benzimidazole -- acute promyeloblastic leukemia -- choroid plexus carcinoma -- cytotoxicity; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2019.1613987
• Languages: English
• ISSNs: 1475-6366

Abstract

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. Graphical Abstract: