Novel non-hydroxamic histone deactylase (HDAC) inhibitors in development from Miikana

The field of histone deacetylase inhibitors is moving into a new phase of development. LeadDiscovery's report Histone deacetylase inhibitors-Moving from the bench to a promising companion for classic and targeted cancer therapies highlights the biology of the HDACs and the potential of their inhibitors. In profiling the various HDAC inhibitors in development we discuss the toxicological risk of hydroxamic acid, a moiety found in early inhibitors including SAHA. Our strategic evaluation discusses the development of HDAC inhibitors in which the hydroxamic acid has been replaced by other moieties. Here we highlight a series of mercaptoamides being developed by Miikana.

The field of histone deacetylase inhibitors is moving into a new phase of development. The exponential growth in the level of research activity surrounding the histone deacetylases (HDACs) witnessed over the past decade has now started to produce success in the clinic, particularly in the field of oncology. LeadDiscovery's report Histone deacetylase inhibitors-Moving from the bench to a promising companion for classic and targeted cancer therapies highlights the ability of this therapeutic class to block many pathological features that contribute to tumor progression including abnormal cell cycle progression, diminished apoptosis and angiogenesis. The ability of HDAC inhibitors to synergize with classic chemotherapeutic agents as well as newer signal transduction pathway modulators is particularly exciting.

The most advanced therapeutic candidates such as SAHA and FK228 are already showing promising activity. FK228, which is being developed by Gloucester Pharmaceuticals is strategically placed to attain first-in-class status for the niche indications of peripheral T-cell lymphoma and cutaneous T-cell lymphoma.

Adverse effects of first generation inhibitors are primarily hematological (neutropenia and thrombocytopenia) and cardiologic. Toxicology may be due in part to limited selectivity against the large number of HDAC isoenzymes and also the hydroxamic moiety which features in a number of first generation inhibitors. In an attempt to reduce toxicity, MethyGene, one of the leaders in the field of HDAC inhibitors has developed a series of sulfonamide anilides, based on their corresponding hydroxamates.

Miikana Therapeutics is another company involved in the development of non-hydroxamate inhibitors of histone deacetylases and in the featured Bioorg Med Chem Lett paper a series of mercaptoamides with low micromolar inhibitory activity is described. The series was designed to be structurally as close as possible to SAHA, but having the mercaptoamide replacing the hydroxamate moiety. The most potent inhibitor of the series had an IC50 of only 660nM, 10-fold lower than that of SAHA, however further lead optimization studies are underway.

Entry date Tuesday, May 31, 2005

Bioorg Med Chem Lett. 2005 Apr 15;15(8):1969-72.