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Revision as of 06:11, 31 July 2011 editArcadian (talk | contribs)163,050 edits removed Category:Chemotherapeutic agents; added Category:Experimental cancer drugs using HotCat← Previous edit		Latest revision as of 20:22, 28 December 2024 edit undoBobChemist (talk | contribs)5 editsm →Licensing and Clinical developmentTags: Visual edit Newcomer task Newcomer task: update
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			{{Update|date=February 2018}}
	{{chembox		{{chembox
	| Verifiedfields = changed		| Watchedfields = changed
		⚫	| verifiedrevid = 442314042
⚫	| UNII_Ref = {{fdacite|changed|FDA}}
		⚫	| ImageFile=Irofulven.svg
		⚫	| ImageSize=
		⚫	| PIN=(6′''R'')-6′-Hydroxy-3′-(hydroxymethyl)-2′,4′,6′-trimethylspiro-7′(6′''H'')-one
		⚫	| OtherNames=
		⚫	|Section1={{Chembox Identifiers
		⚫	| UNII_Ref = {{fdacite|correct|FDA}}
	| UNII = 6B799IH05A		| UNII = 6B799IH05A
		⚫	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
⚫	| verifiedrevid = 408568500
⚫	|ImageFile=Irofulven.svg
⚫	|ImageSize=
⚫	|IUPACName=(6<nowiki>'</nowiki>''R'')-6'-hydroxy-3'-(hydroxymethyl)-2',4',6'-trimethylspiro-7'(6'''H'')-one
⚫	|OtherNames=
⚫	|Section1= {{Chembox Identifiers
⚫	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 130640		| ChemSpiderID = 130640
	| KEGG_Ref = {{keggcite|correct|kegg}}		| KEGG_Ref = {{keggcite|correct|kegg}}
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	| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}		| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChIKey = NICJCIQSJJKZAH-AWEZNQCLSA-N		| StdInChIKey = NICJCIQSJJKZAH-AWEZNQCLSA-N
			| CASNo_Ref = {{cascite|correct|??}}
	| CASNo=158440-71-2		| CASNo=158440-71-2
	| PubChem=148189		| PubChem=148189
	| SMILES = O=C1C/3=C/C(=C(C\3=C(/C2(1(O)C)CC2)C)CO)C		| SMILES = O=C1C/3=C/C(=C(C\3=C(/C2(1(O)C)CC2)C)CO)C
	}}		}}
	|Section2= {{Chembox Properties		|Section2={{Chembox Properties
	| Formula=C<sub>15</sub>H<sub>18</sub>O<sub>3</sub>		| Formula=C<sub>15</sub>H<sub>18</sub>O<sub>3</sub>
	| MolarMass=246.302 g/mol		| MolarMass=246.302 g/mol
	| Appearance=		| Appearance=
	| Density=		| Density=1.285 g/mL
	| MeltingPt=		| MeltingPt=
	| BoilingPt=		| BoilingPt=
	| Solubility=		| Solubility=
	}}		}}
	|Section3= {{Chembox Hazards		|Section3={{Chembox Hazards
	| MainHazards=		| MainHazards=
	| FlashPt=		| FlashPt=
			| AutoignitionPt =
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⚫	'''Irofulven''' or '''6-hydroxymethylacylfulvene''' (also known as '''HMAF''' of '''MGI-114''') is an antitumor agent.<ref name="pmid18388315">{{cite journal |author=Escargueil AE, Poindessous V, Soares DG, Sarasin A, Cook PR, Larsen AK |title=Influence of irofulven, a transcription-coupled repair-specific antitumor agent, on RNA polymerase activity, stability and dynamics in living mammalian cells |journal=J. Cell. Sci. |volume=121 |issue=Pt 8 |pages=1275–83 |year=2008 |month=April |pmid=18388315 |doi=10.1242/jcs.023259 |url=}}</ref><ref name="pmid8913837">{{cite journal |author=Kelner MJ, McMorris TC, Estes L, Wang W, Samson KM, Taetle R |title=Efficacy of HMAF (MGI-114) in the MV522 metastatic lung carcinoma xenograft model nonresponsive to traditional anticancer agents |journal=Invest New Drugs |volume=14 |issue=2 |pages=161–7 |year=1996 |pmid=8913837 |doi= 10.1007/BF00210787|url=}}</ref> It belongs to the family of ] called ]s.
		⚫	'''Irofulven''' or '''6-hydroxymethylacylfulvene''' (also known as '''HMAF''' of '''MGI-114''') is an experimental antitumor agent.<ref name="pmid18388315">{{ cite journal |author1=Escargueil, A. E. |author2=Poindessous, V. |author3=Soares, D. G. |author4=Sarasin, A. |author5=Cook, P. R. |author6=Larsen, A. K. | title = Influence of Irofulven, a Transcription-Coupled Repair-Specific Antitumor Agent, on RNA Polymerase Activity, Stability and Dynamics in Living Mammalian Cells | journal = Journal of Cell Science | volume = 121 | issue = Pt 8 | pages = 1275–1283 |date=April 2008 | pmid = 18388315 | doi = 10.1242/jcs.023259 |doi-access= |s2cid=9282024 }}</ref><ref name="pmid8913837">{{ cite journal |author1=Kelner, M. J. |author2=McMorris, T. C. |author3=Estes, L. |author4=Wang, W. |author5=Samson, K. M. |author6=Taetle, R. | title = Efficacy of HMAF (MGI-114) in the MV522 Metastatic Lung Carcinoma Xenograft Model Nonresponsive to Traditional Anticancer Agents | journal = Investigational New Drugs | volume = 14 | issue = 2 | pages = 161–167 | year = 1996 | pmid = 8913837 | doi = 10.1007/BF00210787 |s2cid=8439510 }}</ref> It belongs to the family of ] called ]s.
	It inhibits the replication of DNA.<ref name="pmid17118344">{{cite journal |author=Wang Y, Wiltshire T, Senft J, Reed E, Wang W |title=Irofulven induces replication-dependent CHK2 activation related to p53 status |journal=Biochem. Pharmacol. |volume=73 |issue=4 |pages=469–80 |year=2007 |month=February |pmid=17118344 |pmc=1800887 |doi=10.1016/j.bcp.2006.10.023 |url=}}</ref>
			It inhibits the DNA replication of cells deficient in ] in culture.<ref name="pmid17118344">{{ cite journal |author1=Wang, Y. |author2=Wiltshire, T. |author3=Senft, J. |author4=Reed, E. |author5=Wang, W. | title = Irofulven Induces Replication-Dependent CHK2 Activation Related to p53 Status | journal = ] | volume = 73 | issue = 4 | pages = 469–480 |date=February 2007 | pmid = 17118344 | pmc = 1800887 | doi = 10.1016/j.bcp.2006.10.023 }}</ref><ref name=":0">{{Cite journal |last1=Börcsök |first1=Judit |last2=Sztupinszki |first2=Zsofia |last3=Bekele |first3=Raie |last4=Gao |first4=Sizhi P. |last5=Diossy |first5=Miklos |last6=Samant |first6=Amruta S. |last7=Dillon |first7=Kasia M. |last8=Tisza |first8=Viktoria |last9=Spisák |first9=Sándor |last10=Rusz |first10=Orsolya |last11=Csabai |first11=Istvan |last12=Pappot |first12=Helle |last13=Frazier |first13=Zoë J. |last14=Konieczkowski |first14=David J. |last15=Liu |first15=David |date=2021-04-01 |title=Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer |journal=Clinical Cancer Research|volume=27 |issue=7 |pages=2011–2022 |doi=10.1158/1078-0432.CCR-20-3316 |issn=1557-3265 |pmc=8026514 |pmid=33208343}}</ref>
		⚫	Irofulven is an ] of ], a ] toxin found in the Jack 'o' Lantern mushroom ('']''). The compound was originally synthesized by Dr. Trevor McMorris and found to have anticancer properties in mice by Dr. Michael J Kelner.<ref>{{ cite journal |author1=MacDonald, J. R. |author2=Muscoplat, C. C. |author3=Dexter, D. L. |author4=Mangold, G. L. |author5=Chen, S. F. |author6=Kelner, M. J. |author7=McMorris, T. C. |author8=Von Hoff, D. D. | title = Preclinical Antitumor Activity of 6-hydroxymethylacylfulvene, a Semisynthetic Derivative of the Mushroom Toxin Illudin S | journal = Cancer Research | volume = 57 | issue = 2 | pages = 279–283 | year = 1997 | pmid = 9000568 | url = http://cancerres.aacrjournals.org/content/57/2/279.full.pdf }}</ref>
			__TOC__
			==Licensing and Clinical development==
			The drug was created and patented by the ], San Diego (UCSD), and subsequently licensed to the US biotech company MGI Pharma. ] 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 ] and ]. 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.<ref>Schilder RJ et al. (2010 Oct). . J Gynecol Cancer. 20(7):1137-41. {{PMC|3079178}}.</ref> Previously, a European Phase I study in combination with ] 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.<ref>Hilger W et al.(July 2006),. Invest New Drugs. 24(4):311-9. {{doi|10.1007/s10637-005-5055-6}}.</ref>
			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 (]) 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.<ref> Pharmacy Choice - Pharmaceutical News. Retrieved 12 May 2017.</ref>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.<ref>{{Cite web |date=2021-07-27 |title=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 |url=https://ir.lanternpharma.com/news-events/press-releases/detail/54/lantern-pharma-reacquires-rights-to-phase-2-clinical-trial |access-date=2024-07-26 |website=Lantern Pharma Inc. |language=en}}</ref> The study was still ongoing as of late 2024.<ref name=":1">{{Cite web |title=ClinicalTrials.gov |url=https://clinicaltrials.gov/study/NCT03643107 |access-date=2024-12-28 |website=clinicaltrials.gov}}</ref>
			Since it was first synthesized, research with irofulven has decreased dramatically over the past decade with only one clinical trial currently being run.<ref name=":1" /> 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.<ref name=":0" /> Since this discovery, research has increased with researchers calling irofulven a "previously abandoned" anticancer drug.<ref>{{Cite journal |last1=Prosz |first1=Aurel |last2=Duan |first2=Haohui |last3=Tisza |first3=Viktoria |last4=Sahgal |first4=Pranshu |last5=Topka |first5=Sabine |last6=Klus |first6=Gregory T. |last7=Börcsök |first7=Judit |last8=Sztupinszki |first8=Zsofia |last9=Hanlon |first9=Timothy |last10=Diossy |first10=Miklos |last11=Vizkeleti |first11=Laura |last12=Stormoen |first12=Dag Rune |last13=Csabai |first13=Istvan |last14=Pappot |first14=Helle |last15=Vijai |first15=Joseph |date=2023-11-23 |title=Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma |journal=Scientific Reports |language=en |volume=13 |issue=1 |pages=20567 |doi=10.1038/s41598-023-47946-4 |pmid=37996508 |issn=2045-2322|pmc=10667362 |bibcode=2023NatSR..1320567P }}</ref><ref name=":0" /><ref>{{Cite web |date=2021-01-11 |title=Repairing DNA Damage in Cancer Cells {{!}} Memorial Sloan Kettering Cancer Center |url=https://www.mskcc.org/news/repairing-dna-damage-cancer-cells |access-date=2024-01-26 |website=www.mskcc.org |language=en}}</ref>
⚫	Irofulven is an ] of ], a ] toxin found in mushrooms of the ] '']''. The compound was oringally synthesized by Dr. Trevor McMorris (UCSD) and found to have anticancer properties by Dr. Michael J Kelner (UCSD).<ref>{{cite journal |author=MacDonald JR, Muscoplat CC, Dexter DL, Mangold GL, Chen SF, Kelner MJ, McMorris TC, Von Hoff DD |title=Preclinical antitumor activity of 6-hydroxymethylacylfulvene, a semisynthetic derivative of the mushroom toxin illudin S |journal=Cancer Res. |volume=57 |issue=2 |pages=279–83 |year=1997 |pmid=9000568}} </ref>
	==Synthesis==		==Synthesis==
		⚫	A synthesis of irofulven has been reported.<ref>{{ Cite journal | doi = 10.1021/jo035084j | pmid = 14750783 | title = Synthesis and Biological Activity of Enantiomers of Antitumor Irofulven | year = 2004 | last1 = McMorris | first1 = T. C. | last2 = Staake | first2 = M. D. | last3 = Kelner | first3 = M. J. | journal = The Journal of Organic Chemistry | volume = 69 | issue = 3 | pages = 619–23 }}</ref>
	]		:]{{clear left}}
⚫	{{Cite journal|doi=10.1021/jo035084j|pmid=14750783|title=Synthesis and Biological Activity of Enantiomers of Antitumor Irofulven|year=2004|last1=McMorris|first1=Trevor C.|last2=Staake|first2=Michael D.|last3=Kelner|first3=Michael J.|journal=The Journal of Organic Chemistry|volume=69|issue=3|pages=619}}
	==References==		==References==
	{{reflist|2}}		{{reflist}}
	{{Chemotherapeutic agents}}
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