Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2014-10, Vol.57 (20), p.8358-8377

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.