Romidepsin
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MedKoo CAT#: 100764

CAS#: 128517-07-7

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.


Chemical Structure

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Romidepsin
CAS# 128517-07-7

Theoretical Analysis

MedKoo Cat#: 100764
Name: Romidepsin
CAS#: 128517-07-7
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

Price and Availability

Size Price Availability Quantity
1.0mg USD 90.0 Ready to ship
5.0mg USD 250.0 Ready to ship
10.0mg USD 450.0 Ready to ship
25.0mg USD 750.0 Ready to ship
50.0mg USD 1450.0 Ready to ship
100.0mg USD 2450.0 Ready to ship
200.0mg USD 3850.0 Ready to ship
500.0mg USD 5750.0 Ready to ship
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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

Appearance: white to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Romidepsin (FK 228) inhibits HDAC1, HDAC2, HDAC4, and HDAC6 with IC50s of 36 nM, 47 nM, 510 nM and 1.4 μM, respectively.
In vitro activity: The effects of romidepsin on the proliferation, cell cycle and apoptosis of murine colon cancer cell lines were evaluated. CT26 and MC38 cells were treated with or without romidepsin for 24 h, then measured by Brdu cell cycle assay. A dramatic decrease in the number of cells in the S + G2/M phase and a significant increase in the number of cells in the G0/G1 phase after romidepsin treatment was observed (Fig. 1a). Furthermore, the expression level of PCNA was also downregulated, which suggested the proliferation inhibition effects of romidepsin (Fig. 1b). Compared to the control cells, romidepsin-treated cells had a marginal increase in apoptotic events (Fig. 1c), which was validated by the increased caspase 3 cleavage (Fig. 1d). Reference: Cancer Immunol Immunother. 2021 Jan;70(1):61-73. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838139/
In vivo activity: The effects of romidepsin in vivo were examined using subcutaneous tumor-transplanted mice and CAC (colitis-associated cancer) mice. Subcutaneous transplantation tumor mouse models were established by inoculating CT26 cells. After 16 days of treatment with romidepsin, tumor size and weight were obviously reduced compared with the control group (Fig. 2a). The expression of cleaved-caspase 3 in romidepsin-treated group was also upregulated (Fig. 2b). In the CAC model, colon cancer was induced by AOM and 3% DSS treatment for 70 days and then treated with romidepsin three times (Fig. 2c). The average number of tumors per mouse was used as criterion of efficacy, which was divided based on size (< 5 mm and >5 mm in the largest dimension). The average number of tumors > 5 mm per mouse was lower in the romidepsin treatment group than in the control group, while there was no obvious difference in the number of tumors with sizes < 5 mm between the two groups (Fig. 2d). Reference: Cancer Immunol Immunother. 2021 Jan;70(1):61-73. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838139/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 43.85 81.1
DMF 5.0 9.25
DMSO:PBS (pH 7.1) (1:1) 0.5 0.93
Ethanol 10.0 18.49

Preparing Stock Solutions

The following data is based on the product molecular weight 540.7 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Shi Y, Fu Y, Zhang X, Zhao G, Yao Y, Guo Y, Ma G, Bai S, Li H. Romidepsin (FK228) regulates the expression of the immune checkpoint ligand PD-L1 and suppresses cellular immune functions in colon cancer. Cancer Immunol Immunother. 2021 Jan;70(1):61-73. doi: 10.1007/s00262-020-02653-1. Epub 2020 Jul 6. PMID: 32632663; PMCID: PMC7838139.
In vitro protocol: 1. Shi Y, Fu Y, Zhang X, Zhao G, Yao Y, Guo Y, Ma G, Bai S, Li H. Romidepsin (FK228) regulates the expression of the immune checkpoint ligand PD-L1 and suppresses cellular immune functions in colon cancer. Cancer Immunol Immunother. 2021 Jan;70(1):61-73. doi: 10.1007/s00262-020-02653-1. Epub 2020 Jul 6. PMID: 32632663; PMCID: PMC7838139.
In vivo protocol: 1. Shi Y, Fu Y, Zhang X, Zhao G, Yao Y, Guo Y, Ma G, Bai S, Li H. Romidepsin (FK228) regulates the expression of the immune checkpoint ligand PD-L1 and suppresses cellular immune functions in colon cancer. Cancer Immunol Immunother. 2021 Jan;70(1):61-73. doi: 10.1007/s00262-020-02653-1. Epub 2020 Jul 6. PMID: 32632663; PMCID: PMC7838139.

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1. Pattarawat P, Hunt JT, Poloway J, Archibald CJ, Wang HR. A triple combination gemcitabine + romidepsin + cisplatin to effectively control triple-negative breast cancer tumor development, recurrence, and metastasis. Cancer Chemother Pharmacol. 2021 May 27. doi: 10.1007/s00280-021-04298-y. Epub ahead of print. PMID: 34043046.

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.



Additional Information

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.