Resminostat Explained

Resminostat (4SC-201 or RAS2410) is an orally bioavailable inhibitor of histone deacetylases (HDACs), of which inhibitors are antineoplastic agents.^[1]

In 2011, the German drug maker 4SC was granted orphan drug designation for resminostat by the US FDA for the treatment of hepatocellular carcinoma (HCC).^[2]

In 2016, the FDA granted IND for clinical tests in combination with sorafenib for HCC.^[3] 4SC say "In several phase I and phase II trials, resminostat has already demonstrated very good safety and tolerability, alongside promising indications of efficacy."^[3]

Clinical trials

Resminostat has undergone a phase I/II clinical trial for K-ras mutated advanced colorectal carcinoma.^[4]

It has undergone a phase II clinical trial for relapsed or refractory Hodgkin's lymphoma.^[5]

Mechanism

Resminostat restrains the phosphorylation of 4E-BP1 and p70S6k, indicating a disturbance with Akt signalling pathway. The treatment of resminostat leads to a drop of Bim and Bax protein level and Bcl-xL level.^[6]

As with other HDAC inhibitors such as pracinostat, 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.

Notes and References

1. Histone deacetylase inhibitors in hepatocellular carcinoma: A therapeutic perspective. 2018. Elsevier Surg Oncol 2018 Dec;27(4):611-618.doi: 10.1016/j.suronc.2018.07.015.Epub 2018 Jul 30.. 30449480. Tsilimigras. D. I.. Ntanasis-Stathopoulos. I.. Moris. D.. Spartalis. E.. Pawlik. T. M.. Surgical Oncology. 27. 4. 611–618. 10.1016/j.suronc.2018.07.015. 53947365.
2. Web site: 4SC's Anti-Cancer Drug Resminostat achieves Median Overall Survival of 8.0 Months in Second-Line Advanced Liver Cancer (HCC) Patients. September 2012.
3. http://pipelinereview.com/index.php/2016022460511/Small-Molecules/4SC-AG-FDA-approves-IND-application-for-resminostat-in-liver-cancer.html 4SC AG: FDA approves IND application for resminostat in liver cancer. Feb 2016
4. https://clinicaltrials.gov/ct2/show/NCT01277406 4SC-201 (Resminostat) in Advanced Colorectal Carcinoma (SHORE)
5. https://clinicaltrials.gov/ct2/show/NCT01037478 Resminostat (4SC-201) in Relapsed or Refractory Hodgkin's Lymphoma (SAPHIRE)
6. First-in-human, pharmacokinetic and pharmacodynamic phase I study of Resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors.. 10.1158/1078-0432.CCR-13-0735 . Brunetto AT, etal . 19. 19. 5494–504. 1 Oct 2013. 3790647. 24065624. Clin Cancer Res.