Resminostat (4SC-201 or RAS2410) is an orally bioavailable inhibitor of

histone deacetylase Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important becaus ...

s (HDACs), of which inhibitors are

antineoplastic agent Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a cura ...

s. In 2011, the German drug maker 4SC was granted

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

designation for resminostat by the

US FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

for the treatment of

hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. HCC most common ...

(HCC). In 2016, the FDA granted

IND Ind or IND may refer to: General * Independent (politician), a politician not affiliated to any political party * Independent station, used within television program listings and the television industry for a station that is not affiliated with ...

for clinical tests in combination with

sorafenib Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer (hepatocellular carcinoma), FLT3-ITD positive AML and ra ...

for HCC.4SC AG: FDA approves IND application for resminostat in liver cancer. Feb 2016
/ref> 4SC say "In several phase I and phase II trials, resminostat has already demonstrated very good safety and tolerability, alongside promising indications of efficacy."

Clinical trials

Resminostat has undergone a phase I/II clinical trial for K-ras mutated advanced

colorectal carcinoma Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...

. It has undergone a phase II clinical trial for relapsed or refractory

Hodgkin's lymphoma Hodgkin lymphoma (HL) is a type of lymphoma in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the lymph nodes. The condition was named a ...

Mechanism

Resminostat restrains the

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

4E-BP1 Eukaryotic translation initiation factor 4E-binding protein 1 (also known as 4E-BP1) is a protein that in humans is encoded by the ''EIF4EBP1'' gene. inhibits cap-dependent translation by binding to translation initiation factor eIF4E. Phosphoryl ...

and

p70S6k Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase (p70S6K, p70-S6K), is an enzyme (specifically, a protein kinase) that in humans is encoded by the ''RPS6KB1'' gene. It is a serine/threonine kinase that acts downstream of Phos ...

, indicating a disturbance with Akt signalling pathway. The treatment of resminostat leads to a drop of Bim and Bax protein level and

Bcl-xL B-cell lymphoma-extra large (Bcl-xL), encoded by the BCL2-like 1 gene, is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondr ...

level. As with other

HDAC inhibitor Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases. Since deacetylation of histones produces transcriptionally silenced heterochromatin, HDIs can render chromatin more transcri ...

s such as pracinostat, the inhibition of HDACs by resminostat results in an accumulation of highly acetylated

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...

s, followed by an abduction of

chromatin remodeling Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...

, inhibition of tumor suppressor genes transcription and

cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...

, and finally tumor cell apoptosis.

References

{{HDAC inhibitors Histone deacetylase inhibitors Sulfonamides Hydroxamic acids Experimental drugs Pyrroles