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|Title:||ST7612AA1, a thioacetate-ω(γ-lactam carboxamide) derivative selected from a novel generation of oral HDAC inhibitors||Authors:||Giannini, G.
Milazzo, F. M.
Guglielmi, M. B.
|Keywords:||amide; carboplatin; histone deacetylase inhibitor; prodrug; romidepsin; ST 7612AA1; thiol derivative; unclassified drug; 2 pyrrolidone derivative; anilide; antineoplastic agent; HDAC8 protein, human; histone; histone deacetylase; histone deacetylase 3; histone deacetylase inhibitor; repressor protein; thioacetic acid S-(6-((5-oxopyrrolidine-2-carbonyl)amino)-6-phenylcarbamoylhexyl) ester; tubulin||Issue Date:||2014||Project:||None||Journal:||JOURNAL OF MEDICINAL CHEMISTRY||Abstract:||
A systematic study of medicinal chemistry aimed at identifying a new generation of HDAC inhibitors, through the introduction of a thiol zinc-binding group (ZBG) and of an amide-lactam in the ω-position of the polyethylene chain of the vorinostat scaffold, allowed the selection of a new class of potent pan-HDAC inhibitors (pan-HDACis). Simple, highly versatile, and efficient synthetic approaches were used to synthesize a library of these new derivatives, which were then submitted to a screening for HDAC inhibition as well as to a preliminary in vitro assessment of their antiproliferative activity. Molecular docking into HDAC crystal structures suggested a binding mode for these thiol derivatives consistent with the stereoselectivity observed upon insertion of amide-lactam substituents in the ω-position. ST7612AA1 (117), selected as a drug candidate for further development, showed an in vitro activity in the nanomolar range associated with a remarkable in vivo antitumor activity, highly competitive with the most potent HDAC inhibitors, currently under clinical trials. A preliminary study of PK and metabolism is also illustrated.
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