Romidepsin

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Romidepsin
Skeletal formula of (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone
Romidepsin ball and spoke.png
Systematic (IUPAC) name
(1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone
Clinical data
Trade names Istodax
MedlinePlus a610005
Licence data US FDA:link
Pregnancy cat.
Legal status
Routes Intravenous infusion
Pharmacokinetic data
Bioavailability Not applicable (IV only)
Protein binding 92–94%
Metabolism Hepatic (mostly CYP3A4-mediated)
Half-life 3 hours
Identifiers
CAS number 128517-07-7 N
ATC code None
PubChem CID 5352062
UNII CX3T89XQBK N
ChEBI CHEBI:61080 N
ChEMBL CHEMBL1213490 N
Synonyms FK228; FR901228; Istodax
Chemical data
Formula C24H36N4O6S2 
Mol. mass 540.695 g/mol
 N (what is this?)  (verify)

Romidepsin (INN, trade name Istodax), codenamed FK228 and FR901228, is an anticancer agent undergoing clinical trials as a treatment for cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma, and a variety of other cancers. Romidepsin is a natural product obtained from the bacteria Chromobacterium violaceum, and works by blocking enzymes known as histone deacetylases and inducing apoptosis.[1] It is sometimes referred to as depsipeptide, after the class of molecules to which it belongs.

Romidepsin is branded and owned by Gloucester Pharmaceuticals, now a part of Celgene.[2] On November 5, 2009, it was approved by the U.S. Food and Drug Administration for the treatment of CTCL, after five years in the agency's fast track development program.

History[edit]

Romidepsin was first reported in the scientific literature in 1994, by a team of researchers from Fujisawa Pharmaceutical Company (now Astellas Pharma) in Tsukuba, Japan, who isolated it in a culture of Chromobacterium violaceum from a soil sample obtained in Yamagata Prefecture.[3] It was found to have little to no antibacterial activity, but was potently cytotoxic against several human cancer cell lines, with no effect on normal cells; studies on mice later found it to have antitumor activity in vivo as well.[3]

The first total synthesis of romidepsin was accomplished by Harvard researchers and published in 1996.[4] Its mechanism of action was elucidated in 1998, when researchers from Fujisawa and the University of Tokyo found it to be a histone deacetylase inhibitor with effects similar to those of trichostatin A.[5]

Clinical trials[edit]

Phase I studies of romidepsin began in 1997, sponsored by the National Cancer Institute.[6]

Phase II trials were conducted for a variety of indications, including prostate cancer, multiple myeloma, pancreatic cancer,[6] breast cancer,[7] ovarian cancer,[8] melanoma,[9] neuroendocrine tumors,[10] and leukemias.[11] The most dramatic results were found in the treatment of cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs).[6]

In 2004, romidepsin received Fast Track designation from the FDA for the treatment of cutaneous T-cell lymphoma, and orphan drug status from the FDA and the European Medicines Agency for the same indication;[6]

2009: FDA approval for CTCL was obtained on November 5, 2009.[12]

As of November 2009, 3 phase II trials for multiple myeloma and peripheral T-cell lymphoma are still recruiting.[13][14][15]

Mechanism of action[edit]

Romidepsin acts as a prodrug with the disulfide bond undergoing reduction within the cell to release a zinc-binding thiol.[3][16][17] The thiol reversibly interacts with a zinc atom in the binding pocket of Zn-dependent histone deacetylase to block its activity. Thus it is an HDAC inhibitor. Many HDAC inhibitors are potential treatments for cancer through the ability to restore normal expression of genes, which may result in cell cycle arrest, differentiation, and apoptosis.[18]

Adverse effects[edit]

The use of romidepsin is uniformly associated with adverse effects.[19] In clinical trials, the most common were nausea and vomiting, fatigue, infection, loss of appetite, and blood disorders (including anemia, thrombocytopenia, and leukopenia). It has also been associated with metabolic disturbances (such as abnormal electrolyte levels), skin reactions, altered taste perception, and changes in cardiac electrical conduction.[19]

References[edit]

  1. ^ "Romidepsin". National Cancer Institute. Retrieved 2009-09-11. 
  2. ^ "Romidepsin". Gloucester Pharmaceuticals. Retrieved 2009-09-11. 
  3. ^ a b c Ueda H, Nakajima H, Hori Y, et al. (March 1994). "FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity". Journal of Antibiotics 47 (3): 301–10. doi:10.7164/antibiotics.47.301. PMID 7513682. 
  4. ^ Li KW, Wu J, Xing W, Simon JA (July 1996). "Total synthesis of the antitumor depsipeptide FR-901,228". Journal of the American Chemical Society 118 (30): 7237–8. doi:10.1021/ja9613724. 
  5. ^ Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S (May 1998). "FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor". Experimental Cell Research 241 (1): 126–33. doi:10.1006/excr.1998.4027. PMID 9633520. 
  6. ^ a b c d Masuoka Y, Shindoh N, Inamura N (2008). "Histone deacetylase inhibitors from microorganisms: the Astellas experience". In Petersen F, Amstutz R. Natural compounds as drugs 2. Basel: Birkhäuser. pp. 335–59. ISBN 978-3-7643-8594-1.  Retrieved on November 8, 2009 through Google Book Search.
  7. ^ ClinicalTrials.gov NCT00098397 . Retrieved on November 8, 2009.
  8. ^ ClinicalTrials.gov NCT00085527 . Retrieved on November 8, 2009.
  9. ^ ClinicalTrials.gov NCT00104884 . Retrieved on November 8, 2009.
  10. ^ ClinicalTrials.gov NCT00084461 . Retrieved on November 8, 2009.
  11. ^ ClinicalTrials.gov NCT00062075 . Retrieved on November 8, 2009.
  12. ^ http://chembl.blogspot.com/2009/11/new-drug-approvals-pt-xxiii-romidepsin.html
  13. ^ ClinicalTrials.gov NCT00765102 . Retrieved on November 8, 2009.
  14. ^ ClinicalTrials.gov NCT00426764 . Retrieved on November 8, 2009.
  15. ^ ClinicalTrials.gov NCT00924378 . Retrieved on November 8, 2009.
  16. ^ Shigematsu, N.; Ueda, H.; Takase, S.; Tanaka, H.; Yamamoto, K.; Tada, T. (1994). "FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. II. Structure determination.". J. Antibiot. 47 (3): 311–314. doi:10.7164/antibiotics.47.311. PMID 8175483. 
  17. ^ Ueda, H.; Manda, T.; Matsumoto, S.; Mukumoto, S.; Nishigaki, F.; Kawamura, I.; Shimomura, K. (1994). "FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. III. Antitumor activities on experimental tumors in mice.". J. Antibiot. 47 (3): 315–323. doi:10.7164/antibiotics.47.315. PMID 8175484. 
  18. ^ Greshock, Thomas J.; Johns, Deidre M.; Noguchi, Yasuo; Williams, Robert M. (2008). "Improved Total Synthesis of the Potent HDAC Inhibitor FK228 (FR-901228)". Organic Letters 10 (4): 613–616. doi:10.1021/ol702957z. PMC 3097137. PMID 18205373. 
  19. ^ a b [No authors listed] (November 2009). "ISTODEX Label Information". U.S. Food and Drug Administration. Retrieved 2009-11-07. 

External links[edit]