ST7612AA1, a Thioacetate-ω(γ-lactam carboxamide) Derivative Selected from a Novel Generation of Oral HDAC Inhibitors
| Autor: | Ferdinando Maria Milazzo, Walter Cabri, Silvia Rivara, Gianfranco Battistuzzi, Maurizio Taddei, Daniele Pala, Giuseppe Giannini, Marco Mor, Marcella Barbarino, Mose Santaniello, Loredana Vesci, Nicola Fanto, Davide Vignola, Mario B. Guglielmi, Claudio Pisano |
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| Přispěvatelé: | Giuseppe Giannini*†, Loredana Vesci†, Gianfranco Battistuzzi†, Davide Vignola†, Ferdinando M. Milazzo†, Mario Berardino Guglielmi, Marcella Barbarino, Mosè Santaniello, Nicola Fantò, Marco Mor, Silvia Rivara, Daniele Pala‡p, Maurizio Taddei, Claudio Pisano, Cabri W |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Administration
Oral Carboxamide Chemistry Techniques Synthetic Romidepsin HDAC8 protein Histones chemistry.chemical_compound Tubulin Drug Discovery Anilides antineoplastic agent Chemistry repressor protein Epigenetic Prodrug Pyrrolidinones unclassified drug thiol derivative Molecular Docking Simulation Hdac carboplatin Lactam Molecular Medicine Female prodrug medicine.drug medicine.drug_class Stereochemistry Mice Nude Antineoplastic Agents histone anilide Histone Deacetylases histone deacetylase 3 ST 7612AA1 2 pyrrolidone derivative thioacetic acid S-(6-((5-oxopyrrolidine-2-carbonyl)amino)-6-phenylcarbamoylhexyl) ester In vivo medicine romidepsin Animals Humans human histone deacetylase inhibitor Vorinostat HCT116 Cells amide Xenograft Model Antitumor Assays Histone Deacetylase Inhibitors Repressor Proteins HDAC8 protein human histone deacetylase tubulin Stereoselectivity Histone deacetylase Drug Screening Assays Antitumor |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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