Chemistry:Irofulven

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

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

Irofulven is an analogue of 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, now known as Allarty Therapeutics A/S.

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, Allarty 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. Allarty 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] In 2021, Lantern Pharma reacquired the rights to the development and commercialization of irofulven. At that time, 9 of the intended 27 patients had been a part of the study which saw an increase of median overall survival from 2.6 to 5.4 months.[9] The study was still ongoing as of late 2024.[10]

Since it was first synthesized, research with irofulven has decreased dramatically over the past decade with only one clinical trial currently being run.[10] 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.[11][4][12]

Synthesis

A synthesis of irofulven has been reported.[13]

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Mechanism

Using the AP-site-sequencing method click-code-seq, researchers from ETH Zurich found that irofulven-induced DNA modifications accumulate predominantly in AA dimers and promoters as well as non-transcribed strands of genes, which likely reflects the action of TC-NER.[14]

References

  1. ↑ Escargueil, A. E.; Poindessous, V.; Soares, D. G.; Sarasin, A.; Cook, P. R.; Larsen, A. K. (April 2008). "Influence of Irofulven, a Transcription-Coupled Repair-Specific Antitumor Agent, on RNA Polymerase Activity, Stability and Dynamics in Living Mammalian Cells". Journal of Cell Science 121 (Pt 8): 1275–1283. doi:10.1242/jcs.023259. PMID 18388315. 
  2. ↑ Kelner, M. J.; McMorris, T. C.; Estes, L.; Wang, W.; Samson, K. M.; Taetle, R. (1996). "Efficacy of HMAF (MGI-114) in the MV522 Metastatic Lung Carcinoma Xenograft Model Nonresponsive to Traditional Anticancer Agents". Investigational New Drugs 14 (2): 161–167. doi:10.1007/BF00210787. PMID 8913837. 
  3. ↑ Wang, Y.; Wiltshire, T.; Senft, J.; Reed, E.; Wang, W. (February 2007). "Irofulven Induces Replication-Dependent CHK2 Activation Related to p53 Status". Biochemical Pharmacology 73 (4): 469–480. doi:10.1016/j.bcp.2006.10.023. PMID 17118344. 
  4. ↑ 4.0 4.1 4.2 Börcsök, Judit; Sztupinszki, Zsofia; Bekele, Raie; Gao, Sizhi P.; Diossy, Miklos; Samant, Amruta S.; Dillon, Kasia M.; Tisza, Viktoria et al. (2021-04-01). "Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer". Clinical Cancer Research 27 (7): 2011–2022. doi:10.1158/1078-0432.CCR-20-3316. ISSN 1557-3265. PMID 33208343. 
  5. ↑ MacDonald, J. R.; Muscoplat, C. C.; Dexter, D. L.; Mangold, G. L.; Chen, S. F.; Kelner, M. J.; McMorris, T. C.; Von Hoff, D. D. (1997). "Preclinical Antitumor Activity of 6-hydroxymethylacylfulvene, a Semisynthetic Derivative of the Mushroom Toxin Illudin S". Cancer Research 57 (2): 279–283. PMID 9000568. http://cancerres.aacrjournals.org/content/57/2/279.full.pdf. 
  6. ↑ Schilder, Russell J.; Blessing, John A.; Shahin, Mark S.; Miller, David S.; Tewari, Krishnansu Sujata; Muller, Carolyn Y.; Warshal, David P.; McMeekin, Scott et al. (October 2010). "A phase 2 evaluation of irofulven as second-line treatment of recurrent or persistent intermediately platinum-sensitive ovarian or primary peritoneal cancer: a Gynecologic Oncology Group trial". International Journal of Gynecological Cancer 20 (7): 1137–1141. doi:10.1111/igc.0b013e3181e8df36. ISSN 1525-1438. PMID 21495215. 
  7. ↑ Hilgers, Werner; Faivre, Sandrine; Chieze, Stéphanie; Alexandre, Jérôme; Lokiec, François; Goldwasser, François et al. (July 2006). "A phase I and pharmacokinetic study of irofulven and cisplatin administered in a 30-min infusion every two weeks to patients with advanced solid tumors" (in en). Investigational New Drugs 24 (4): 311–319. doi:10.1007/s10637-005-5055-6. ISSN 0167-6997. PMID 16683074. https://link.springer.com/10.1007/s10637-005-5055-6. 
  8. ↑ "Both Danish sites now open in the Screening Study of prostate cancer patients for OV's Irofulven". http://www.pharmacychoice.com/news/article.cfm?Article_ID=1610062. 
  9. ↑ "Lantern Pharma Reacquires Rights to Phase 2 Clinical Trial in Metastatic Prostate Cancer and Global Development & Commercialization of Irofulven (LP-100) from Allarity Therapeutics A/S" (in en). 2021-07-27. https://ir.lanternpharma.com/news-events/press-releases/detail/54/lantern-pharma-reacquires-rights-to-phase-2-clinical-trial. 
  10. ↑ 10.0 10.1 Allarity Therapeutics. "Phase II Study of Irofulven in AR-targeted and Docetaxel-Pretreated Metastatic Castration-Resistant Prostate Cancer Patients, Who Have a Drug Response Predictor (DRP®) Indicating a High Likelihood of Response to Irofulven.". https://clinicaltrials.gov/study/NCT03643107. 
  11. ↑ Prosz, Aurel; Duan, Haohui; Tisza, Viktoria; Sahgal, Pranshu; Topka, Sabine; Klus, Gregory T.; Börcsök, Judit; Sztupinszki, Zsofia et al. (2023-11-23). "Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma" (in en). Scientific Reports 13 (1): 20567. doi:10.1038/s41598-023-47946-4. ISSN 2045-2322. PMID 37996508. Bibcode: 2023NatSR..1320567P. 
  12. ↑ "Repairing DNA Damage in Cancer Cells | Memorial Sloan Kettering Cancer Center" (in en). 2021-01-11. https://www.mskcc.org/news/repairing-dna-damage-cancer-cells. 
  13. ↑ McMorris, T. C.; Staake, M. D.; Kelner, M. J. (2004). "Synthesis and Biological Activity of Enantiomers of Antitumor Irofulven". The Journal of Organic Chemistry 69 (3): 619–23. doi:10.1021/jo035084j. PMID 14750783. 
  14. ↑ Takhaveev, Vakil; Püllen, Nikolai J. L.; Singh, Navnit K.; Lefevre, Lucie; Aghajani, Emilie A.; Huber, Sabrina M.; Schauer, Stefan; Gahlon, Hailey L. et al. (2025-10-31). "Click-code-seq reveals strand biases of DNA oxidation and depurination in human genome" (in en). Nature Chemical Biology: 1–12. doi:10.1038/s41589-025-02052-6. ISSN 1552-4469. PMID 41174235. https://www.nature.com/articles/s41589-025-02052-6. 



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