Vorinostat Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
Vorinostat is the first drug in a new class of anti-cancer agents that inhibit
histone deacetylases (HDAC). It was launched as an oral treatment for
cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL)
who have progressive, persistent, or recurrent disease on or following two
systemic therapies. HDACs are enzymes that catalyze the removal of the acetyl
modification on lysine residues of proteins, including the core nucleosomal
histones. Together with their counterpart histone acetyltransferases (HATs),
HDACs regulate the acetylation level of the histones, which plays an important
role in the regulation of chromatin plasticity and gene transcription. Hypoacetylation
of histones is associated with a condensed chromatin structure
resulting in the repression of gene transcription, whereas acetylated histones are
associated with a more open chromatin structure and activation of transcription.
In some cancer cells, there is an overexpression of HDACs, resulting in hypoacetylation
of histones. Inhibitors of HDAC are thought to transcriptionally
reactivate dormant tumor-suppressor genes by allowing for the accumulation of
acetyl groups on histones and an open chromatin structure. Vorinostat inhibits
the enzymatic activity of HDAC1, HDAC2, HDAC3, and HDAC6 at nanomolar
concentrations (IC50 ＜86 nM). In vitro, it induces growth arrest, differentiation or
apoptosis in a variety of tumor cells. In addition, vorinostat inhibits tumor
growth in animal models bearing solid tumors, including breast, prostate, lung
and gastric cancers, as well as hematologic malignancies such as multiple
myeloma and leukemias.
Chemische Eigenschaften
White Crystalline Solid
Verwenden
Vorinostat, a histone deacetylase (HDAC) inhibitor from
Merck, was approved for the treatment of cutaneous T-cell
lymphoma (CTCL), a type of non-Hodgkin’s lymphoma.
Vorinostat was shown to inhibit HDAC1, HDAC2, HDAC3
and HDAC6 at nanomolar concentrations. HDAC inhibitors
are potent differentiating agents toward a variety of neoplasms,
including leukemia and breast and prostate cancers.
Definition
ChEBI: A dicarboxylic acid diamide comprising suberic (octanedioic) acid coupled to aniline and hydroxylamine. A histone deacetylase inhibitor, it is marketed under the name Zolinza for the treatment of cutaneous T cell lymphoma (CTCL).
Allgemeine Beschreibung
Histones are proteins around which DNA is wound in the process of packing DNA into the nucleus. They also havea role in regulating the transcription of genes, and this iscontrolled by the covalent modifications acetylation, phosphorylation,and methylation to which they are subject.
Vorinostat fits the basic pharmacophore for the HDACis, which consists of a hydrophobic cap regionconnected to a zinc coordinating functionality by a hydrophobiclinker.The hydroxamic acid functionality iscapable of bidendate binding to zinc present in the enzymeand is a major factor in the overall binding of the compound.The compound inhibits HDAC1, 2, 3, and 6 classes of thisenzyme with nanomolar (＜86 nM) IC50 values.
The agent is given orally and is available in 100-mg capsulesfor the treatment of cutaneous T-cell lymphoma. Thebioavailability is 43%, and the agent is 71% bound toplasma proteins. Extensive metabolism of the agent occursto give the O-glucuronide of the hydroxamic acid functionand 4-anilino-4-oxobutanoic acid with minimal involvementof isozymes of CYP. The metabolites, both of whichare inactive, are eliminated in the urine and the drug has aterminal elimination half-life of 2 hours. The most commonlyreported adverse effects are fatigue, diarrhea, andnausea.
Vorinostat Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
