Romidepsin

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
Clinical data
Trade names Istodax
Synonyms FK228; FR901228; Istodax
MedlinePlus a610005
License data
Pregnancy
category
  • US: D (Evidence of risk)
    Routes of
    administration    		 Intravenous infusion
    ATC code
    • none
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability Not applicable (IV only)
    Protein binding 92–94%
    Metabolism Hepatic (mostly CYP3A4-mediated)
    Elimination half-life 3 hours
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    ChemSpider
    UNII
    ChEBI
    ChEMBL
    ECHA InfoCard 100.211.884 Edit this at Wikidata
    Chemical and physical data
    Formula C24H36N4O6S2
    Molar mass 540.695 g/mol
    3D model (JSmol)
     ☒N☑Y (what is this?)  (verify)

    Romidepsin, also known as Istodax, is an anticancer agent used in cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs). Romidepsin is a natural product obtained from the bacterium Chromobacterium violaceum, and works by blocking enzymes known as histone deacetylases, thus 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]

    History

    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

    Phase I studies of romidepsin, initially codenamed FK228 and FR901228, began in 1997.[6] Phase II and phase III trials were conducted for a variety of indications. The most significant 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]

    The FDA approved romidepsin for CTCL in November 2009[7] and approved romidepsin for other peripheral T-cell lymphomas (PTCLs) in June 2011.[8]

    Pre-clinical HIV study

    In 2014, PLOS Pathogens published a study involving romidepsin in a trial designed to reactivate latent HIV virus in order to deplete the HIV reservoir. Latently infected T-cells were exposed in vitro and ex vivo to romidepsin, leading to an increase in detectable levels of cell-associated HIV RNA. The trial also compared the effect of romidepsin to another histone deacetylase inhibitor, Vorinostat [9]

    Autism study in animal model

    A study involving romidepsin in an animal study that showed that a brief treatment with low amounts of romidepsin could reverse social deficits in a mouse model of autism.[10]

    Mechanism of action

    Romidepsin acts as a prodrug with the disulfide bond undergoing reduction within the cell to release a zinc-binding thiol.[3][11][12] The thiol binds to 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 epigenetically restore normal expression of tumor suppressor genes, which may result in cell cycle arrest, differentiation, and apoptosis.[13]

    Adverse effects

    The use of romidepsin is uniformly associated with adverse effects.[14] 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 infections, and with metabolic disturbances (such as abnormal electrolyte levels), skin reactions, altered taste perception, and changes in cardiac electrical conduction.[14]

    References

    1. ↑ "Romidepsin". National Cancer Institute. Retrieved 2009-09-11.
    2. ↑ "Romidepsin". Gloucester Pharmaceuticals. Retrieved 2009-09-11.
    3. 1 2 3 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. 1 2 3 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. ↑ http://chembl.blogspot.com/2009/11/new-drug-approvals-pt-xxiii-romidepsin.html
    8. ↑ http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Reports.MonthlyApprovalsAll
    9. ↑ Wei, D etal., (2014). ""Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing"". PLoS Pathog. 10 (4): e1004071. doi:10.1371/journal.ppat.1004071. PMC 3983056. PMID 24722454.
    10. ↑ Qin, Luye; Ma, Kaijie; Wang, Zi-Jun; Hu, Zihua; Matas, Emmanuel; Wei, Jing; Yan, Zhen (2018). "Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition". Nature Neuroscience. 21 (4): 564. doi:10.1038/s41593-018-0110-8. PMID 29531362.
    11. ↑ 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.
    12. ↑ 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.
    13. ↑ 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.
    14. 1 2 [No authors listed] (October 2014). "ISTODEX Label Information (updated to October 2014)" (PDF). U.S. Food and Drug Administration.
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