WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 100764
Description: Romidepsin, also known as FK228; is a bicyclic depsipeptide antibiotic isolated from the bacterium Chromobacterium violaceum with antineoplastic activity. After intracellular activation, romidepsin binds to and inhibits histone deacetylase (HDAC), resulting in alterations in gene expression and the induction of cell differentiation, cell cycle arrest, and apoptosis. This agent also inhibits hypoxia-induced angiogenesis and depletes several heat shock protein 90 (Hsp90)-dependent oncoproteins.
MedKoo Cat#: 100764
Chemical Formula: C24H36N4O6S2
Exact Mass: 540.20763
Molecular Weight: 540.7
Elemental Analysis: C, 53.31; H, 6.71; N, 10.36; O, 17.75; S, 11.86
Synonym: FK228; FK-228; FK 228; FR901228; FR-901228; FR 901228; NSC 630176. depsipeptide; US brand name: Istodax.
IUPAC/Chemical Name: (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16ene-3,6,9,19,22-pentone
InChi Key: OHRURASPPZQGQM-GCCNXGTGSA-N
InChi Code: InChI=1S/C24H36N4O6S2/c1-6-16-21(30)28-20(14(4)5)24(33)34-15-9-7-8-10-35-36-12-17(22(31)25-16)26-23(32)19(13(2)3)27-18(29)11-15/h6-7,9,13-15,17,19-20H,8,10-12H2,1-5H3,(H,25,31)(H,26,32)(H,27,29)(H,28,30)/b9-7+,16-6-/t15-,17-,19-,20+/m1/s1
SMILES Code: O=C([C@H](C(C)C)NC(/C(N1)=C/C)=O)O[C@](CC(N[C@H](C(C)C)C(N2)=O)=O)([H])/C=C/CCSSC[C@]2([H])C1=O
Romidepsin, a histone deacetylase (HDAC) inhibitor, is a bicyclic depsipeptide. At room temperature, romidepsin is a white powder and is described chemically as (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16ene-3,6,9,19,22-pentone. The empirical formula is C24H36N4O6S2. ISTODAX (romidepsin) for injection is intended for intravenous infusion only after reconstitution with the supplied Diluent and after further dilution with 0.9% Sodium Chloride, USP. ISTODAX is supplied as a kit containing two vials. ISTODAX (romidepsin) for injection is a sterile lyophilized white powder and is supplied in a single-use vial containing 10 mg romidepsin and 20 mg povidone, USP. Diluent for ISTODAX is a sterile clear solution and is supplied in a single-use vial containing a 2-mL deliverable volume. Diluent for ISTODAX contains 80% (v/v) propylene glycol, USP and 20% (v/v) dehydrated alcohol, USP.
According to http://en.wikipedia.org/wiki/Romidepsin, 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. 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. The first total synthesis of romidepsin was accomplished by Harvard researchers and published in 1996. 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. Romidepsin is branded and owned by Gloucester Pharmaceuticals, now a part of Celgene. 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.
Mechanism of Action
Romidepsin is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors. In vitro, romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines with IC50 values in the nanomolar range. The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized.
1: Saijo K, Imamura J, Narita K, Oda A, Shimodaira H, Katoh T, Ishioka C. Biochemical, biological, and structural properties of romidepsin (FK228) and its analogs as novel HDAC/PI3K dual inhibitors. Cancer Sci. 2014 Dec 10. doi: 10.1111/cas.12585. [Epub ahead of print] PubMed PMID: 25492515.
2: Foss F, Coiffier B, Horwitz S, Pro B, Prince HM, Sokol L, Greenwood M, Lerner A, Caballero D, Baran E, Kim E, Nichols J, Balser B, Wolfson J, Whittaker S. Tolerability to romidepsin in patients with relapsed/refractory T-cell lymphoma. Biomark Res. 2014 Sep 8;2:16. doi: 10.1186/2050-7771-2-16. eCollection 2014. PubMed PMID: 25279222; PubMed Central PMCID: PMC4181623.
3: Oda A, Saijo K, Ishioka C, Narita K, Katoh T, Watanabe Y, Fukuyoshi S, Takahashi O. Predicting the structures of complexes between phosphoinositide 3-kinase (PI3K) and romidepsin-related compounds for the drug design of PI3K/histone deacetylase dual inhibitors using computational docking and the ligand-based drug design approach. J Mol Graph Model. 2014 Nov;54:46-53. doi: 10.1016/j.jmgm.2014.08.007. Epub 2014 Sep 8. PubMed PMID: 25254927.
4: Yu P, Petrus MN, Ju W, Zhang M, Conlon KC, Nakagawa M, Maeda M, Bamford RN, Waldmann TA. Augmented efficacy with the combination of blockade of the Notch-1 pathway, bortezomib and romidepsin in a murine MT-1 adult T-cell leukemia model. Leukemia. 2014 Aug 14. doi: 10.1038/leu.2014.241. [Epub ahead of print] PubMed PMID: 25118879.
5: Finn N, Larouche JF. Romidepsin used as monotherapy in sequence with allogeneic stem cell transplant in a patient with peripheral T-cell lymphoma. Case Rep Hematol. 2014;2014:404078. doi: 10.1155/2014/404078. Epub 2014 Jul 7. PubMed PMID: 25105035; PubMed Central PMCID: PMC4109362.
6: Satwani P, Bavishi S, Saha A, Zhao F, Ayello J, van de Ven C, Chu Y, Cairo MS. Upregulation of NKG2D ligands in acute lymphoblastic leukemia and non-Hodgkin lymphoma cells by romidepsin and enhanced in vitro and in vivo natural killer cell cytotoxicity. Cytotherapy. 2014 May 20. pii: S1465-3249(14)00548-9. doi: 10.1016/j.jcyt.2014.03.008. [Epub ahead of print] PubMed PMID: 24856896.
7: Romidepsin is effective and well-tolerated in patients ≥60 years old with relapsed or refractory peripheral T-cell lymphoma (PTCL): analysis from phase 2 trials. Clin Adv Hematol Oncol. 2014 Feb;12(2 Suppl 5):17-8. PubMed PMID: 24852793.
8: Wei DG, Chiang V, Fyne E, Balakrishnan M, Barnes T, Graupe M, Hesselgesser J, Irrinki A, Murry JP, Stepan G, Stray KM, Tsai A, Yu H, Spindler J, Kearney M, Spina CA, McMahon D, Lalezari J, Sloan D, Mellors J, Geleziunas R, Cihlar T. 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. 2014 Apr 10;10(4):e1004071. doi: 10.1371/journal.ppat.1004071. eCollection 2014 Apr. PubMed PMID: 24722454; PubMed Central PMCID: PMC3983056.
9: Karthik S, Sankar R, Varunkumar K, Ravikumar V. Romidepsin induces cell cycle arrest, apoptosis, histone hyperacetylation and reduces matrix metalloproteinases 2 and 9 expression in bortezomib sensitized non-small cell lung cancer cells. Biomed Pharmacother. 2014 Apr;68(3):327-34. doi: 10.1016/j.biopha.2014.01.002. Epub 2014 Jan 15. PubMed PMID: 24485799.
10: Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, Caballero D, Morschhauser F, Wilhelm M, Pinter-Brown L, Padmanabhan Iyer S, Shustov A, Nielsen T, Nichols J, Wolfson J, Balser B, Horwitz S. Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol Oncol. 2014 Jan 23;7(1):11. doi: 10.1186/1756-8722-7-11. PubMed PMID: 24456586; PubMed Central PMCID: PMC4016573.