ST7612AA1, a Thioacetate-ω(γ-lactam carboxamide) Derivative Selected from a Novel Generation of Oral HDAC Inhibitors

• Published in: Journal of medicinal chemistry Vol. 57; no. 20; pp. 8358 - 8377
• Main Authors: Giannini, Giuseppe, Vesci, Loredana, Battistuzzi, Gianfranco, Vignola, Davide, Milazzo, Ferdinando M, Guglielmi, Mario Berardino, Barbarino, Marcella, Santaniello, Mosè, Fantò, Nicola, Mor, Marco, Rivara, Silvia, Pala, Daniele, Taddei, Maurizio, Pisano, Claudio, Cabri, Walter
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.10.2014; Amer Chemical Soc
• Subjects: Administration, Oral; Anilides - administration & dosage; Anilides - pharmacology; Animals; Antineoplastic Agents - pharmacology; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Drug Screening Assays, Antitumor; Female; HCT116 Cells; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - chemistry; Histones - metabolism; Humans; Life Sciences & Biomedicine; Mice, Nude; Molecular Docking Simulation; Pharmacology & Pharmacy; Pyrrolidinones - administration & dosage; Pyrrolidinones - pharmacology; Repressor Proteins - chemistry; Science & Technology; Tubulin - metabolism; Xenograft Model Antitumor Assays; DESIGN; HISTONE DEACETYLASE INHIBITORS; ANALOGS; ACIDS; SUBSTRATE; VORINOSTAT
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5008209

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.