Small-molecule chromatin-modifying agents: Therapeutic applications

摘要

Suberoylanilide hydroxamic acid (vorinostat) was the first of the histone deacetylase inhibitors (HDACi) to be entered as therapy for the treatment of cutaneous T-cell lymphoma. Since then, a number of HDACi belonging to the short-chain fatty acid, hydroxamate, cyclic peptide or benzamide classes have been investigated in Phase II or III clinical trials (alone or in combination) for the treatment of many kinds of tumors. In addition, HDACi can be useful in antimalarial and antifungal therapies, and can reactivate HIV-1 expression in latent cellular reservoirs, thus suggesting that they could be used in combination with highly active antiretroviral therapy. Moreover, they have also proved their efficacy in neurodegenerative diseases, such as Huntingtons disease, Parkinsons disease and Friedreichs ataxia. In particular, a new series of bis-anilides demonstrating a peculiar mechanism of action displayed highly beneficial effects against Huntingtons disease and Friedreichs ataxia. In addition, a number of sirtuin inhibitors demonstrated antiproliferative effects in cell assays as well as in mouse tumor models, thus suggesting a role of such compounds in therapy against cancer. Furthermore, the SIRT2-selective AGK-2 has been reported to have protective effects against Parkinsons disease, and resveratrol and other sirtuin activators can be useful for the treatment of Alzheimers disease.