Wednesday, April 15, 2015

Drugs in Clinical Pipeline: Resminostat

Resminostat [(E)-3-(1-((4-((dimethylamino)methyl)phenyl)sulfonyl)-1H-pyrrol-3-yl)-N-hydroxyacrylamide] is an orally bioavailable inhibitor of histone deacetylases (HDACs) with potential antineoplastic activity.

The inhibition of HDACs by resminostat results in an accumulation of highly acetylated histones, followed by an abduction of chromatin remodeling, inhibition of tumor suppressor genes transcription and cell division, and finally tumor cell apoptosis.

Resminostat is a potent inhibitor of HDACs 1, 3 and 6 [IC50 = 43-72 nmol/l] representing HDAC classes I and II and induces hyperacetylation of histone H4 in MM cells. Low micromolar concentrations of resminostat abrogated cell growth and strongly induced apoptosis (IC50 = 2.5-3 micromol/l in 3 out of 4 MM cell lines) in MM cell lines as well as primary MM cells. At 1 micromol/l, resminostat inhibited proliferation and induced G0/G1 cell cycle arrest in 3 out of 4 MM cell lines accompanied with decreased levels of cyclin D1, cdc25a, Cdk4 and pRb as well as upregulation of p21. Resminostat decreased phosphorylation of 4E-BP1 and p70S6k indicating an interference with Akt pathway signalling [1].

Resminostat is developed by 4SC in Europe and its Japanese development partner Yakult Honsha in Asia-has been investigated to date in a broad clinical Phase I/II programme in the four indications of liver cancer (hepatocellular carcinoma, HCC), Hodgkin Lymphoma (HL), colorectal cancer (CRC), and non-small-cell lung cancer (NSCLC). In all trials, the compound showed good safety and tolerability as well as promising anti-tumour activity both as monotherapy and in combination with other cancer therapies.

In preclinical studies, Resminostat has been shown to effectively inhibit epithelial-mesenchymal transition (EMT). EMT, which may be promoted through the administration of certain conventional cancer therapies, leads to the formation of particularly aggressive tumour cells, which ultimately may result in greater proliferation of cancer cells in patients and the patients' death. HDAC inhibitors modify the three-dimensional chromatin DNA structure of tumour cells and can trigger cell differentiation, which can ultimately result in programmed cell death (apoptosis). HDAC inhibitors therefore offer a mechanism of action that has the potential to halt tumour progression and induce tumour regression. Furthermore, Resminostat-due to its epigenetic mode of action-can develop an additional synergetic effect in combined treatments with other traditional cancer therapies and also fight the development of resistance to other cancer medications [2].

1. Mandl-Weber, S.; et. al. The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells. Br J Haematol 2010, 149(4), 518-528.
2. Resminostat