Preclinical antitumor activity of ST7612AA1: a new oral thiol-based histone deacetylase (HDAC) inhibitor
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Loredana Vesci1,*, Elena Bernasconi2,*, Ferdinando Maria Milazzo1, Rita De Santis1, Eugenio Gaudio2, Ivo Kwee2,3, Andrea Rinaldi2, Silvia Pace1, Valeria Carollo4, Giuseppe Giannini1 and Francesco Bertoni2,5
1 Research & Development, Sigma-Tau, Pomezia, Italy
2 Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland
3 Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland
4 Hysto-Cyto Service srl, Rome, Italy
5 Lymphoma Unit, IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
* These two Authors equally contributed to this work
Loredana Vesci, email:
Francesco Bertoni, email:
Keywords: histone deacetylase inhibitor, anti-tumor, oral, preclinical, tumor models
Received: November 12, 2014 Accepted: December 24, 2014 Published: December 25, 2014
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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