ロミデプシン 化学特性,用途語,生産方法
効能
抗悪性腫瘍薬, ヒストン脱アセチル化酵素阻害薬
商品名
イストダックス (セルジーン)
説明
The U.S. FDA approved romidepsin (also referredto as FK228) in 2009 for
the treatment of cutaneous T-cell lymphoma (CTCL) for patients who
received at least one systemic therapy.
Romidepsin is a natural product that was
first isolated from the fermentation broth of C. violaceum. Romidepsin is the
second histone deacetylase (HDAC) inhibitor approved for CTCL, the other
being vorinostat,whichwas approved by the FDA in 2006. Unlike vorinostat
which is a pan-HDAC inhibitor, romidepsin shows modest selectivity for
class I HDACs in in vitro assays. It has been shown that after romidepsin
enters the cytoplasm, the disulfide bond is cleaved by glutathione to release
the sulfhydryl groupwhich chelateswith the activesite zinc of class IHDACs
and inhibits the enzymatic activity at nanomolar concentrations.
Although romidepsin inhibits class I HDACs, it is 17–23 times less potent as
the parent than the corresponding reduced form at each isozyme. For example,
the IC
50 of romidepsin at HDAC1 is 36±16nM while that of the reduced form is IC
50=1.6± 0.9nM.Romidepsinhasalsobeenshownto induce cell cycle arrest, differentiation, and apoptosis in tumor cells by mechanisms
that cannot be completely explained by HDAC inhibition alone.
化学的特性
Pale Yellow Solid
使用
Labelled Romidepsin (R425060). Romidepsin is a histone deacetylase inhibitor that can alter chromatin structure and gene transcription leading to multiple changes in cellular protein production. This
may result in cell cycle arrest and tumor growth inhibition. Romidepsin has shown anti-proliferative activity in vitro against multiple mouse and human tumor cell lines and in vivo in human tumor xeno
graft models. Romidepsin can be administered with a second agent, such as a cytotoxic agent, a steroidal agent, a proteasome inhibitor, or a kinase inhibitor.
定義
ChEBI: A cyclodepsipeptide consisting of the cyclic disulfide of (2Z)-2-aminobut-2-enoyl, L-valyl, (3S,4E)-3-hydroxy-7-sulfanylhept-4-enoyl, D-valyl and D-cystei
yl residues coupled in sequence and cyclised head-to tail.
臨床応用
Romidepsin, a histone deacetylase inhibitor, originally developed by Fujisawa (now Astellas
Pharma), causes cell cycle arrest, differentiation, and apoptosis in various cancer cells. In 2004,
the FDA granted fast-track designation for romidepsin as monotherapy for the treatment of cutaneous Tcell
lymphoma (CTCL) in patients who have relapsed following, or become refractory to, other systemic
therapies. The FDA designated romidepsin as an orphan drug and it was approved in 2009 for this
indication and it was commercialized in 2010. In 2007, another fast-track designation was granted for
the product as monotherapy of previously treated peripheral T-cell lymphoma. Romidepsin (FR901228)
was originally discovered and isolated from the fermentation broth of Chromobacterium violaceum No.
968. It was identified through efforts in the search for novel agents which selectively reverse the
morphological phenotype of Ras oncogene-transformed cells since the Ras signaling pathway plays a
critical role in cancer development. Therefore, the drug could also have multiple molecular targets for
its anticancer activity besides HDAC. FR901228 is a bicyclic depsipeptide which is structurally
unrelated to any known class of cyclic peptides with an unusual disulfide bond connecting a thiol and Dcysteine.
ロミデプシン 上流と下流の製品情報
原材料
準備製品