Irofulven

Source: Wikipedia, the free encyclopedia.
Irofulven
Names
Preferred IUPAC name
(6′R)-6′-Hydroxy-3′-(hydroxymethyl)-2′,4′,6′-trimethylspiro[cyclopropane-1,5′-inden]-7′(6′H)-one
Identifiers
3D model (
JSmol
)
ChEMBL
ChemSpider
KEGG
UNII
  • InChI=1S/C15H18O3/c1-8-6-10-12(11(8)7-16)9(2)15(4-5-15)14(3,18)13(10)17/h6,16,18H,4-5,7H2,1-3H3/t14-/m0/s1 checkY
    Key: NICJCIQSJJKZAH-AWEZNQCLSA-N checkY
  • InChI=1/C15H18O3/c1-8-6-10-12(11(8)7-16)9(2)15(4-5-15)14(3,18)13(10)17/h6,16,18H,4-5,7H2,1-3H3/t14-/m0/s1
    Key: NICJCIQSJJKZAH-AWEZNQCLBL
  • O=C1C/3=C/C(=C(C\3=C(/C2([C@]1(O)C)CC2)C)CO)C
Properties
C15H18O3
Molar mass 246.302 g/mol
Density 1.285 g/mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Irofulven or 6-hydroxymethylacylfulvene (also known as HMAF of MGI-114) is an experimental antitumor agent.[1][2] It belongs to the family of drugs called alkylating agents.

It inhibits the DNA replication of cells deficient in nucleotide excision repair in culture.[3][4]

Irofulven is an

illudin S, a sesquiterpene toxin found in the Jack 'o' Lantern mushroom (Omphalotus illudens). The compound was originally synthesized by Dr. Trevor McMorris and found to have anticancer properties in mice by Dr. Michael J Kelner.[5]

Licensing and Clinical development

The drug was created and patented by the University of California, San Diego (UCSD), and subsequently licensed to the US biotech company MGI Pharma. Eisai acquired MGI in 2007, and the license was returned to UCSD, which then re-licensed the potential cancer drug to Lantern Pharma in 2015. Soon after, the drug was again sub-licensed to Oncology Venture.

The drug has undergone a number of clinical trials, mostly for late-stage tumors as well as ovarian and prostate cancers, usually preceded by treatment with carboplatin and paclitaxel. A multi-center phase 2 trial involving patients with Recurrent or Persistent Ovarian Epithelial or Primary Peritoneal Cancer was well tolerated but irofluven demonstrated modest activity as a single agent.[6] Previously, a European Phase I study in combination with cisplatin showed substantial evidence for anti-tumor activity. In that study, irofulven showed rapid elimination and high interpatient variability. Platinum and irofulven pharmacokinetics did not suggest drug-drug interactions.[7]

Despite modest successes demonstrating limited efficacy for late stage tumors that were statistically not significant enough to support broader clinical trials, Oncology Venture has decided to stratify patient populations with companion diagnostic tools (

biomarkers) to predict outcomes, and thus select that sub-set of patients through DRP (Drug Response Predictors), for whom treatment with irofulven would be most effective. Oncology Venture Sweden AB has initiated two Phase 2 drug-screening studies at two Danish University Hospitals for late-stage prostate cancers, wherein 300 patients have been included to be screened, of which only 27 are to be selected for the Phase 2 trial.[8] This clinical trial is still ongoing with an expected completion date of mid 2024.[9]

Since it was first synthesized, research with irofulven has decreased dramatically over the past decade with only one clinical trial currently being run.[9] A study published in 2021 showed cells with nucleotide excision repair (NER) deficiencies were susceptible to iroflaven while cells without these NER deficiencies were not overly affected. The deficiency of tumors in NER was seen as a potential identifier for patient candidates.[4] Since this discovery, research has increased with researchers calling irofulven a "previously abandoned" anticancer drug.[10][4][11]

Synthesis

A synthesis of irofulven has been reported.[12]

References

  1. S2CID 9282024
    .
  2. S2CID 8439510
    .
  3. PMID 17118344
    .
  4. ^
    PMID 33208343
    .
  5. PMID 9000568
    .
  6. PMC 3079178
    .
  7. doi:10.1007/s10637-005-5055-6
    .
  8. ^ Both Danish sites now open in the Screening Study of prostate cancer patients for OV's Irofulven Pharmacy Choice - Pharmaceutical News. Retrieved 12 May 2017.
  9. ^ a b "ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2024-01-26.
  10. PMID 37996508
    .
  11. ^ "Repairing DNA Damage in Cancer Cells | Memorial Sloan Kettering Cancer Center". www.mskcc.org. 2021-01-11. Retrieved 2024-01-26.
  12. PMID 14750783
    .
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