title: ST7612AA1, a thioacetate-ω(γ-lactam carboxamide) derivative selected from a novel generation of oral HDAC inhibitors.
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.
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite SpA , Via Pontina Km 30,400, I-00040 Pomezia, Roma, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Loredana
authors.initials: L
authors.lastname: Vesci
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Battistuzzi
authors.forename: Davide
authors.initials: D
authors.lastname: Vignola
authors.forename: Ferdinando M
authors.initials: FM
authors.lastname: Milazzo
authors.forename: Mario Berardino
authors.initials: MB
authors.lastname: Guglielmi
authors.forename: Marcella
authors.initials: M
authors.lastname: Barbarino
authors.forename: Mosè
authors.initials: M
authors.lastname: Santaniello
authors.forename: Nicola
authors.initials: N
authors.lastname: Fantò
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Daniele
authors.initials: D
authors.lastname: Pala
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taddei
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Walter
authors.initials: W
authors.lastname: Cabri
mesh_terms: D000284:Administration, Oral; D000813:Anilides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D004354:Drug Screening Assays, Antitumor; D005260:Female; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry; D006657:Histones / Q000378:metabolism; D006801:Humans; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology*; D012097:Repressor Proteins / Q000737:chemistry; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099186:Histone Deacetylase 3
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D011760:Pyrrolidinones; D012097:Repressor Proteins; D014404:Tubulin; D000099186:Histone Deacetylase 3; C000597472:thioacetic acid S-(6-((5-oxopyrrolidine-2-carbonyl)amino)-6-phenylcarbamoylhexyl) ester; C409470:HDAC8 protein, human