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Ref Type Journal Article
PMID (25671299)
Authors Vesci L, Bernasconi E, Milazzo FM, De Santis R, Gaudio E, Kwee I, Rinaldi A, Pace S, Carollo V, Giannini G, Bertoni F
Title Preclinical antitumor activity of ST7612AA1: a new oral thiol-based histone deacetylase (HDAC) inhibitor.
Journal Oncotarget
Vol 6
Issue 8
Date 2015 Mar 20
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
ST7612AA1 ST7612AA1 9 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
ST7612AA1 HDAC Inhibitor 38 ST7612AA1 is a second-generation pan-HDAC inhibitor, which leads to decreased proliferation and increased apoptosis of tumor cells (PMID: 25671299, PMID: 32039017).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown ovarian cancer not applicable ST7612AA1 Preclinical - Cell line xenograft Actionable In a preclinical study, ST7612AA1 inhibited proliferation of ovarian cancer cell lines in culture, and inhibited tumor growth in ovarian cancer cell line xenograft models (PMID: 25671299). 25671299
Unknown unknown lung non-small cell carcinoma not applicable ST7612AA1 Preclinical - Cell line xenograft Actionable In a preclinical study, ST7612AA1 inhibited proliferation of non-small cell lung cancer (NSCLC) cell lines in culture, and inhibited tumor growth in NSCLC cell line xenograft models (PMID: 25671299). 25671299
Unknown unknown mantle cell lymphoma not applicable ST7612AA1 Preclinical Actionable In a preclinical study, ST7612AA1 inhibited proliferation of mantle cell lymphoma cell lines in culture (PMID: 25671299). 25671299
Unknown unknown diffuse large B-cell lymphoma not applicable ST7612AA1 Preclinical Actionable In a preclinical study, ST7612AA1 inhibited proliferation of diffuse large B-cell lymphoma cell lines in culture (PMID: 25671299). 25671299
Unknown unknown splenic marginal zone lymphoma not applicable ST7612AA1 Preclinical Actionable In a preclinical study, ST7612AA1 inhibited proliferation of splenic marginal zone lymphoma cell lines in culture (PMID: 25671299). 25671299
Unknown unknown chronic myeloid leukemia not applicable ST7612AA1 Preclinical Actionable In a preclinical study, ST7612AA1 inhibited proliferation of chronic myeloid leukemia cells in culture (PMID: 25671299). 25671299
Unknown unknown colorectal cancer not applicable ST7612AA1 Preclinical - Cell line xenograft Actionable In a preclinical study, ST7612AA1 inhibited proliferation of colon cancer cells in culture, and inhibited tumor growth in colon cancer cell line xenograft models (PMID: 25671299). 25671299
Unknown unknown acute myeloid leukemia not applicable ST7612AA1 Preclinical - Cell line xenograft Actionable In a preclinical study, ST7612AA1 inhibited proliferation of acute myeloid leukemia (AML) cell lines in culture and demonstrated antitumor activity in AML cell line xenograft models (PMID: 25671299). 25671299
Unknown unknown breast cancer not applicable ST7612AA1 Preclinical - Cell line xenograft Actionable In a preclinical study, ST7612AA1 inhibited proliferation of breast cancer cell lines in culture, and inhibited tumor growth in breast cancer cell line xenograft models (PMID: 25671299). 25671299