title: Preclinical antitumor activity of ST7612AA1: a new oral thiol-based histone deacetylase (HDAC) inhibitor.
abstract: ST7612AA1 (property of Sigma-Tau), a thioacetate-ω (γ-lactam amide) derivative, is a potent, second generation, oral pan-histone deacetylase inhibitor (HDACi). Aim of the study was to assess the efficacy of ST7612AA1 in solid and haematological tumors, and to characterize its mechanism of action. In vitro, ST7612AA1 potently inhibited different class I and class II HDACs, leading to restore the balance of both histone and non-histone protein acetylation. In vivo, it induced significant anti-tumor effects in xenograft models of lung, colon, breast and ovarian carcinomas, leukemia and lymphoma. This was likely due to the modulation of different HDAC substrates and induction of transcriptional changes with respect to several genes involved in key processes, such as cell cycle regulation, DNA damage checkpoints, immune response, cell adhesion and epithelial-to-mesenchymal transition. PK analysis confirmed the pro-drug nature of ST7612AA1, which is rapidly absorbed and converted to ST7464AA1 after a single oral dose in mice. ST7612AA1 was selected from a novel generation of oral HDAC inhibitors. Its high efficacy correlated with its potent and selective inhibitory activity of HDAC and was combined with a favorable pharmacodynamics profile. These aspects support a clinical development of ST7612AA1 towards a broad spectrum of human solid and haematologic malignancies.
authors: Research & Development, Sigma-Tau, Pomezia, Italy.
authors: Loredana
authors: L
authors: Vesci
authors: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors: Elena
authors: E
authors: Bernasconi
authors: Research & Development, Sigma-Tau, Pomezia, Italy.
authors: Ferdinando Maria
authors: FM
authors: Milazzo
authors: Research & Development, Sigma-Tau, Pomezia, Italy.
authors: Rita
authors: R
authors: De Santis
authors: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors: Eugenio
authors: E
authors: Gaudio
authors: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.|Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland.
authors: Ivo
authors: I
authors: Kwee
authors: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors: Andrea
authors: A
authors: Rinaldi
authors: Research & Development, Sigma-Tau, Pomezia, Italy.
authors: Silvia
authors: S
authors: Pace
authors: Hysto-Cyto Service srl, Rome, Italy.
authors: Valeria
authors: V
authors: Carollo
authors: Research & Development, Sigma-Tau, Pomezia, Italy.
authors: Giuseppe
authors: G
authors: Giannini
authors: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.|Lymphoma Unit, IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors: Francesco
authors: F
authors: Bertoni
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011760:Pyrrolidinones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D011760:Pyrrolidinones; C000597472:thioacetic acid S-(6-((5-oxopyrrolidine-2-carbonyl)amino)-6-phenylcarbamoylhexyl) ester
keywords: anti-tumor; histone deacetylase inhibitor; oral; preclinical; tumor models