Vorinostat (

rINN Rinn is a municipality in the district of Innsbruck-Land in the Austrian state of Tyrol located 6 km southeast of Innsbruck. The village was mentioned in documents as “Runne” in 1250 for the first time. Population Climate Climate typ ...

) also known as Suberoylanilide hydroxamic acid ( suberoyl+

anilide Anilides (or phenylamides) are a class of chemical compounds, which are amide derivatives of aniline. Preparation Aniline reacts with acyl chlorides or carboxylic anhydrides to give anilides. For example, reaction of aniline with acetyl chlorid ...

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 deacetylases (HDAC).

Histone deacetylase inhibitor Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases. HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are bei ...

s (HDI) have a broad spectrum of epigenetic activities. Vorinostat is marketed under the name Zolinza ( ) by Merck for the treatment of cutaneous manifestations in patients with

cutaneous T cell lymphoma Cutaneous T-cell lymphoma (CTCL) is a class of non-Hodgkin lymphoma, which is a type of cancer of the immune system. Unlike most non-Hodgkin lymphomas (which are generally B-cell-related), CTCL is caused by a mutation of T cells. The cancerous ...

(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

Medical uses

Vorinostat was the first

histone deacetylase inhibitor Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases. HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are bei ...

approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) for the treatment of CTCL on October 6, 2006. It also failed to demonstrate efficacy in treating

acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may inclu ...

in a phase II study.

Development

In 1966,

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 respo ...

published her observation that a suspension of murine erythroleukemia cells underwent cytodifferentiation to normal erythrocytes when treated with

dimethylsulfoxide Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula ( CH3)2. This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and ...

(DMSO, a common drug solvent and

cryoprotectant A cryoprotectant is a substance used to protect biological tissue from freezing damage (i.e. that due to ice formation). Arctic and Antarctic insects, fish and amphibians create cryoprotectants ( antifreeze compounds and antifreeze proteins) in ...

frequently used for cell culture freezing) at 280 mmolar. Memorial Sloan-Kettering researcher Paul Marks approached Columbia University chemist

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 deacetylases 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 Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality cha ...

, 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 Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to s ...

(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 syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...

s in combination with

idarubicin Idarubicin or 4-demethoxydaunorubicin is an anthracycline antileukemic drug. It inserts itself into DNA and prevents DNA unwinding by interfering with the enzyme topoisomerase II. It is an analog of daunorubicin, but the absence of a methoxy ...

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 i ...

Preclinical investigations

Vorinostat is being investigated as a potential

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

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 cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

s, both ''in vitro'' and ''in vivo.'' Vorinostat also has shown some activity against the pathophysiological changes in α₁-antitrypsin deficiency and cystic fibrosis. 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 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 Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and res ...

, or HPV.

References

External links

Vorinostat bound to proteins
in the PDB {{HDAC inhibitors Anilides Antineoplastic drugs Histone deacetylase inhibitors Merck & Co. brands Hydroxamic acids Orphan drugs