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| {{Chembox
| | '''Luminespib''' is a small molecule inhibitor of heat shock protein 90 (Hsp90), a molecular chaperone involved in the proper folding, stability, and function of many client proteins, including several oncogenic proteins. Luminespib is being investigated for its potential use in the treatment of various types of cancer. |
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| | verifiedrevid = 462257909
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| | ImageFile = Luminespib.svg
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| | ImageSize = 200px
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| | IUPACName = 5-(2,4-Dihydroxy-5-isopropyl-phenyl)-''N''-ethyl-4-[4-(morpholinomethyl)phenyl]isoxazole-3-carboxamide
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| | OtherNames = NVP-AUY-922; AUY922; VER-52296
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| | Section1 = {{Chembox Identifiers
| | ==Mechanism of Action== |
| | CASNo = 747412-49-3
| | Luminespib binds to the ATP-binding domain of [[Hsp90]], inhibiting its chaperone activity. This leads to the degradation of client proteins that are dependent on Hsp90 for stability and function. Many of these client proteins are involved in [[cell signaling]] pathways that promote [[tumor growth]] and survival, such as [[HER2]], [[EGFR]], and [[AKT]]. By inhibiting Hsp90, luminespib disrupts these pathways, leading to [[apoptosis]] and reduced proliferation of cancer cells. |
| | CASNo_Ref = {{cascite|changed|??}}
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| | ChEBI_Ref = {{ebicite|correct|EBI}}
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| | ChEBI = 83656
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| | ChEMBL_Ref = {{ebicite|correct|EBI}}
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| | ChEMBL = 252164
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| | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
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| | StdInChI = 1S/C26H31N3O5/c1-4-27-26(32)24-23(18-7-5-17(6-8-18)15-29-9-11-33-12-10-29)25(34-28-24)20-13-19(16(2)3)21(30)14-22(20)31/h5-8,13-14,16,30-31H,4,9-12,15H2,1-3H3,(H,27,32)
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| | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
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| | StdInChIKey = NDAZATDQFDPQBD-UHFFFAOYSA-N
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| | PubChem = 135539077
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| | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
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| | ChemSpiderID = 21377936
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| | KEGG_Ref = {{keggcite|correct|kegg}}
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| | KEGG = D10646
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| | UNII = C6V1DAR5EB
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| | DrugBank = DB11881
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| | SMILES = CC(C)c1cc(c(O)cc1O)c2onc(C(=O)NCC)c2c3ccc(cc3)CN4CCOCC4
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| | InChI = InChI=1S/C26H31N3O5/c1-4-27-26(32)24-23(18-7-5-17(6-8-18)15-29-9-11-33-12-10-29)25(34-28-24)20-13-19(16(2)3)21(30)14-22(20)31/h5-8,13-14,16,30-31H,4,9-12,15H2,1-3H3,(H,27,32)
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| | Section2 = {{Chembox Properties
| | ==Pharmacokinetics== |
| | C=26 | H=31 | N=3 | O=5
| | Luminespib is administered intravenously and has a complex pharmacokinetic profile. It is extensively metabolized in the liver, primarily by [[cytochrome P450]] enzymes. The drug and its metabolites are excreted in both urine and feces. The half-life of luminespib varies depending on the dose and schedule of administration. |
| | Appearance = Colorless solid<ref name=Brough>{{cite journal | doi = 10.1021/jm701018h | title = 4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer | year = 2008 | last1 = Brough | first1 = Paul A. | last2 = Aherne | first2 = Wynne | last3 = Barril | first3 = Xavier | last4 = Borgognoni | first4 = Jenifer | last5 = Boxall | first5 = Kathy | last6 = Cansfield | first6 = Julie E. | last7 = Cheung | first7 = Kwai-Ming J. | last8 = Collins | first8 = Ian | last9 = Davies | first9 = Nicholas G. M. | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 2 | pages = 196–218 | pmid = 18020435 }}</ref>
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| | Section3 = {{Chembox Hazards
| | ==Clinical Trials== |
| | MainHazards =
| | Luminespib has been evaluated in several [[clinical trials]] for the treatment of different types of cancer, including [[breast cancer]], [[lung cancer]], and [[melanoma]]. In these trials, luminespib has shown activity in tumors that are resistant to other therapies, particularly those that overexpress Hsp90 client proteins. |
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| '''Luminespib''' ([[International Nonproprietary Name|INN]],<ref>{{cite web|title=WHO Drug Information. International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 70|url=http://www.who.int/medicines/publications/druginformation/innlists/RL70.pdf|publisher=World Health Organization|accessdate=16 July 2016|pages=297–8}}</ref> previously known as '''NVP-AUY922''') is an experimental drug candidate for the treatment of cancer. It was discovered through a collaboration between The [[Institute of Cancer Research]] and the pharmaceutical company [[Vernalis plc|Vernalis]]<ref>{{cite web | url = http://www.icr.ac.uk/about_us/annual_research_report/9719.pdf | title = Structure-based design of cancer therapeutics | publisher = The Institute of Cancer Research}}</ref> and licensed to [[Novartis]].<ref>{{cite web|url=http://www.vernalis.com/development/oncology/auy922 |title=AUY922 |publisher=Vernalis |deadurl=yes |archiveurl=https://web.archive.org/web/20110929015547/http://www.vernalis.com/development/oncology/auy922 |archivedate=2011-09-29 |df= }}</ref> From 2011 to 2014 it was in Phase II clinical trials.<ref>{{cite web | url = http://www.ft.com/intl/cms/s/0/715446aa-b219-11e0-9d80-00144feabdc0.html#axzz1TL06XsgO | title = Small caps: Vernalis drug fillip | publisher = ''Financial Times'' | date = July 19, 2011}}</ref><ref name=Sidera2014rev>{{cite journal |author1=Sidera, K. |author2=Patsavoudi, E. | title = HSP90 inhibitors: current development and potential in cancer therapy. | journal = Recent Pat. Anticancer Drug Discov. | volume = 9 | issue = 1 | pages = 1–20 |date=Jan 2014 | pmid = 23312026 | pmc = | doi = 10.2174/15748928113089990031 | url = http://www.eurekaselect.com/108016/article}}</ref> Chemically it is a [[Resorcinol|resorcinylic]] isoxazole amide<ref name=Sidera2014rev/>
| | ===Breast Cancer=== |
| | In patients with [[HER2-positive breast cancer]], luminespib has demonstrated the ability to reduce tumor size and delay disease progression. It is often studied in combination with other [[chemotherapeutic agents]] to enhance its efficacy. |
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| Luminespib is an [[enzyme inhibitor|inhibitor]] of [[heat shock protein 90]] (Hsp90),<ref name=Brough/> which is a chaperone protein that plays a role in the modification of a variety of proteins that have been implicated in [[oncogenesis]]. Luminespib has shown promising activity in preclinical testing against several different tumor types.<ref>{{cite journal | doi = 10.1186/bcr1996 | title = NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models | year = 2008 | last1 = Jensen | first1 = Michael | last2 = Schoepfer | first2 = Joseph | last3 = Radimerski | first3 = Thomas | last4 = Massey | first4 = Andrew | last5 = Guy | first5 = Chantale T | last6 = Brueggen | first6 = Josef | last7 = Quadt | first7 = Cornelia | last8 = Buckler | first8 = Alan | last9 = Cozens | first9 = Robert | journal = Breast Cancer Research | volume = 10 | issue = 2 | pages = R33 | pmid = 18430202 | pmc = 2397535 }}</ref><ref>{{cite journal | doi = 10.1158/1535-7163.MCT-09-0683 | title = Mechanistic Evaluation of the Novel HSP90 Inhibitor NVP-AUY922 in Adult and Pediatric Glioblastoma | year = 2010 | last1 = Gaspar | first1 = N. | last2 = Sharp | first2 = S. Y. | last3 = Eccles | first3 = S. A. | last4 = Gowan | first4 = S. | last5 = Popov | first5 = S. | last6 = Jones | first6 = C. | last7 = Pearson | first7 = A. | last8 = Vassal | first8 = G. | last9 = Workman | first9 = P. | journal = Molecular Cancer Therapeutics | volume = 9 | issue = 5 | pages = 1219–1233 | pmid = 20457619 | pmc = 2875164 }}</ref><ref>{{cite journal | pmid = 21508365 | year = 2011 | last1 = Okui | first1 = T | last2 = Shimo | first2 = T | last3 = Hassan | first3 = NM | last4 = Fukazawa | first4 = T | last5 = Kurio | first5 = N | last6 = Takaoka | first6 = M | last7 = Naomoto | first7 = Y | last8 = Sasaki | first8 = A | title = Antitumor effect of novel HSP90 inhibitor NVP-AUY922 against oral squamous cell carcinoma | volume = 31 | issue = 4 | pages = 1197–204 | journal = Anticancer Research }}</ref><ref>{{cite journal | doi = 10.1158/0008-5472.CAN-07-5256 | title = NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis | year = 2008 | last1 = Eccles | first1 = S. A. | last2 = Massey | first2 = A. | last3 = Raynaud | first3 = F. I. | last4 = Sharp | first4 = S. Y. | last5 = Box | first5 = G. | last6 = Valenti | first6 = M. | last7 = Patterson | first7 = L. | last8 = De Haven Brandon | first8 = A. | last9 = Gowan | first9 = S. | journal = Cancer Research | volume = 68 | issue = 8 | pages = 2850–2860 | pmid = 18413753 }}</ref> | | ===Lung Cancer=== |
| | Luminespib has been tested in patients with [[non-small cell lung cancer]] (NSCLC) that harbor mutations in [[EGFR]] or [[ALK]]. These mutations often lead to resistance to standard therapies, and luminespib offers a potential alternative by targeting the Hsp90 chaperone pathway. |
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| A related compound, NVP-HSP990, was abandoned by Novartis in 2012 after it failed to show efficacy in an early clinical trial.<ref name=Sidera2014rev/>
| | ===Melanoma=== |
| | In [[melanoma]], particularly in cases with [[BRAF]] mutations, luminespib has shown promise in preclinical models and early-phase clinical trials. It is being explored as part of combination therapy regimens to overcome resistance to BRAF inhibitors. |
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| ==See also== | | ==Side Effects== |
| * [[Hsp90 inhibitor]]s
| | Common side effects of luminespib include [[fatigue]], [[nausea]], [[diarrhea]], and [[anemia]]. More serious adverse effects can occur, such as [[hepatotoxicity]] and [[cardiotoxicity]], which require careful monitoring during treatment. |
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| ==References== | | ==Future Directions== |
| {{reflist}}
| | Research is ongoing to better understand the full potential of luminespib in cancer therapy. Studies are focusing on identifying biomarkers that predict response to treatment and developing combination strategies to enhance its efficacy and reduce resistance. |
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| [[Category:Carboxamides]] | | ==See Also== |
| | * [[Hsp90 inhibitors]] |
| | * [[Targeted cancer therapy]] |
| | * [[Oncogenic signaling pathways]] |
| | {{pharmacology-stub}} |
| | [[Category:Antineoplastic and immunomodulating agents]] |
| | [[Category:Hsp90 inhibitors]] |
| [[Category:Experimental cancer drugs]] | | [[Category:Experimental cancer drugs]] |
| [[Category:Isoxazoles]]
| | == Luminespib == |
| [[Category:Morpholines]]
| | <gallery> |
| [[Category:Resorcinols]]
| | File:Luminespib.svg|Luminespib |
| | | </gallery> |
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| {{antineoplastic-drug-stub}}
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| {{dictionary-stub1}}
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Luminespib is a small molecule inhibitor of heat shock protein 90 (Hsp90), a molecular chaperone involved in the proper folding, stability, and function of many client proteins, including several oncogenic proteins. Luminespib is being investigated for its potential use in the treatment of various types of cancer.
Mechanism of Action[edit]
Luminespib binds to the ATP-binding domain of Hsp90, inhibiting its chaperone activity. This leads to the degradation of client proteins that are dependent on Hsp90 for stability and function. Many of these client proteins are involved in cell signaling pathways that promote tumor growth and survival, such as HER2, EGFR, and AKT. By inhibiting Hsp90, luminespib disrupts these pathways, leading to apoptosis and reduced proliferation of cancer cells.
Pharmacokinetics[edit]
Luminespib is administered intravenously and has a complex pharmacokinetic profile. It is extensively metabolized in the liver, primarily by cytochrome P450 enzymes. The drug and its metabolites are excreted in both urine and feces. The half-life of luminespib varies depending on the dose and schedule of administration.
Clinical Trials[edit]
Luminespib has been evaluated in several clinical trials for the treatment of different types of cancer, including breast cancer, lung cancer, and melanoma. In these trials, luminespib has shown activity in tumors that are resistant to other therapies, particularly those that overexpress Hsp90 client proteins.
Breast Cancer[edit]
In patients with HER2-positive breast cancer, luminespib has demonstrated the ability to reduce tumor size and delay disease progression. It is often studied in combination with other chemotherapeutic agents to enhance its efficacy.
Lung Cancer[edit]
Luminespib has been tested in patients with non-small cell lung cancer (NSCLC) that harbor mutations in EGFR or ALK. These mutations often lead to resistance to standard therapies, and luminespib offers a potential alternative by targeting the Hsp90 chaperone pathway.
Melanoma[edit]
In melanoma, particularly in cases with BRAF mutations, luminespib has shown promise in preclinical models and early-phase clinical trials. It is being explored as part of combination therapy regimens to overcome resistance to BRAF inhibitors.
Side Effects[edit]
Common side effects of luminespib include fatigue, nausea, diarrhea, and anemia. More serious adverse effects can occur, such as hepatotoxicity and cardiotoxicity, which require careful monitoring during treatment.
Future Directions[edit]
Research is ongoing to better understand the full potential of luminespib in cancer therapy. Studies are focusing on identifying biomarkers that predict response to treatment and developing combination strategies to enhance its efficacy and reduce resistance.
See Also[edit]
Luminespib[edit]
Luminespib
