Vorinostat ( rINN) also known as Suberoylanilide hydroxamic acid ( suberoyl+ anilide+
hydroxamic acid
A hydroxamic acid is a class of organic compounds bearing the functional group RC(O)N(OH)R', with R and R' as organic residues and CO as a carbonyl group. They are amides (RC(O)NHR') wherein the NH center has an OH substitution. They are often us ...
abbreviated as SAHA) is a member of a larger class of compounds that inhibit
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 a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
activities.
Vorinostat is marketed under the name Zolinza ( ) by
Merck
Merck refers primarily to the German Merck family and three companies founded by the family, including:
* the Merck Group, a German chemical, pharmaceutical and life sciences company founded in 1668
** Merck Serono (known as EMD Serono in the Unite ...
for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) when the disease persists, gets worse, or comes back during or after two systemic therapies. The compound was developed by Columbia University chemist
Ronald Breslow
Ronald Charles David Breslow (March 14, 1931 – October 25, 2017) was an American chemist from Rahway, New Jersey. He was University Professor at Columbia University, where he was based in the Department of Chemistry and affiliated with the De ...
and Memorial Sloan-Kettering researcher Paul Marks
Charlotte Friend
Charlotte Friend (March 11, 1921 – January 13, 1987) was an American virologist. She is best known for her discovery of the Friend leukemia virus. She helped to establish the concept of the oncovirus, studied the role of the host immune respon ...
published her observation that a suspension of murine
erythroleukemia
Acute erythrocyte leukemia is a rare form of acute myeloid leukemia (less than 5% of AML cases) where the myeloproliferation is of erythrocytic precursors. It is defined as type "M6" under the FAB classification.
Signs and symptoms
The most com ...
cells underwent cytodifferentiation to normal erythrocytes when treated with dimethylsulfoxide (DMSO, a common drug solvent and cryoprotectant frequently used for
cell culture
Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. The term "tissue culture" was coined by American pathologist Montrose Thomas Burrows. This te ...
freezing) at 280 mmolar. Memorial Sloan-Kettering researcher Paul Marks approached Columbia University chemist
Ronald Breslow
Ronald Charles David Breslow (March 14, 1931 – October 25, 2017) was an American chemist from Rahway, New Jersey. He was University Professor at Columbia University, where he was based in the Department of Chemistry and affiliated with the De ...
about these findings and together they decided to develop more potent analogs of DMSO, in order to make use of this property for cancer treatment. Their optimization process lead to the discovery of suberoylanilide hydroxamic acid and its HDAC-inhibiting property.
Mechanism of action
Vorinostat has been shown to bind to the active site 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 a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
s and act as a chelator for zinc ions also found in the active site of histone deacetylases.
Vorinostat's inhibition of histone deacetylases results in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the expression of genes needed to induce cell differentiation. It acts on class I, II and IV of histone deacetylase.
Clinical trials
Vorinostat has also been used to treat Sézary syndrome, another type of lymphoma closely related to CTCL.
A recent study suggested that vorinostat also possesses some activity against recurrent glioblastoma multiforme, resulting in a median overall survival of 5.7 months (compared to 4–4.4 months in earlier studies). Further brain tumor trials are planned in which vorinostat will be combined with other drugs.
Including vorinostat in treatment of advanced non-small-cell lung carcinoma (NSCLC) showed improved response rates and increased median progression free survival and overall survival.
It has given encouraging results in a phase II trial for myelodysplastic syndromes in combination with idarubicin and
cytarabine
Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by in ...
.
Preclinical investigations
Vorinostat is being investigated as a potential HIV latency reversing agent (LRA) as part of an investigational therapeutic strategy known as "shock and kill." Vorinostat was shown to reactivate HIV in latently HIV-infected T cells, both ''in vitro'' and ''in vivo.''
Vorinostat also has shown some activity against the pathophysiological changes in α1-antitrypsin deficiency and
cystic fibrosis
Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...
.
Recent evidence also suggests vorinostat can be a therapeutic tool for Niemann-Pick type C1 (NPC1), a rare lysosomal lipid storage disease.
Preclinical experiments by University of Alabama at Birmingham researchers suggest the cancer drugs vorinostat,
belinostat
Belinostat (trade name Beleodaq, previously known as PXD101) is a histone deacetylase inhibitor drug developed by TopoTarget for the treatment of hematological malignancies and solid tumors.
It was approved in July 2014 by the US FDA to treat pe ...
and
panobinostat
Panobinostat, sold under the brand name Farydak, is a medication used for the treatment of multiple myeloma. It is a hydroxamic acid and acts as a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor).human papillomavirus, or HPV.
See also
*
Trichostatin A
Trichostatin A (TSA) is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes, but not class III HDACs (i.e., sirtuins). However, there are ...