Luminespib (AUY-922 )

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WARNING: This product is for research use only, not for human or veterinary use.

Description:Luminespib, also known as AUY-922, NVP-AUY922, VER52296, is a derivative of 4,5-diarylisoxazole and a third-generation heat shock protein 90 (Hsp90) inhibitor with potential antineoplastic activity. Hsp90 inhibitor AUY922 has been shown to bind with high affinity to and inhibit Hsp90, resulting in the proteasomal degradation of oncogenic client proteins; the inhibition of cell proliferation; and the elevation of heat shock protein 72 (Hsp72) in a wide range of human tumor cell lines.

Price and Availability

Luminespib (AUY-922 ), purity > 98%, is in stock. The same day shipping out after order is received.

Chemical Structure

Theoretical Analysis

MedKoo Cat#: 200371Name: Luminespib (AUY-922 )CAS#: 747412-49-3Chemical Formula: C26H31N3O5Exact Mass: 465.22637Molecular Weight: 465.54Elemental Analysis:C, 67.08; H, 6.71; N, 9.03; O, 17.18

Synonym:AUY922; AUY-922; AUY 922; NVP AUY922; NVP AUY-922; VER52296 ; VER-52296 ; VER 52296 ; Luminespib

IUPAC/Chemical Name:5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide

InChi Key:NDAZATDQFDPQBD-UHFFFAOYSA-N

InChi Code: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)

SMILES Code:O=C(C1=NOC(C2=CC(C(C)C)=C(O)C=C2O)=C1C3=CC=C(CN4CCOCC4)C=C3)NCC

Technical Data

Additional Information

NVP-AUY922 is  a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (Kd = 1.7 nmol/L) and proliferation of human tumor cells with GI50 values of approximately 2 to 40 nmol/L, inducing G1-G2 arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI50. This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1α, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials. [ source: Cancer Res 2008;68(8):2850–60].    

References

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2: Doi T, Onozawa Y, Fuse N, Yoshino T, Yamazaki K, Watanabe J, AkimovM, Robson M, Boku N, Ohtsu A. Phase I dose-escalation study of the HSP90inhibitor AUY922 in Japanese patients with advanced solid tumors. CancerChemother Pharmacol. 2014 Sep;74(3):629-36. doi:10.1007/s00280-014-2521-x. Epub 2014 Jul 25. PubMed PMID: 25059319;PubMed Central PMCID: PMC4143601.

3: Chiang NJ, Wu SN, Kao CA, Huang YM, Chen LT. Stimulation ofElectroporation-Induced Inward Currents in Glioblastoma Cell Lines bythe Heat Shock Protein Inhibitor AUY922. Clin Exp Pharmacol Physiol.2014 Jun 7. doi: 10.1111/1440-1681.12273. [Epub ahead of print] PubMedPMID: 24909268.

4: Huang J, Sun C, Zhang T, Pan L, Wang S, He Q, Li D. Potent antitumoractivity of HSP90 inhibitor AUY922 in adrenocortical carcinoma. TumourBiol. 2014 May 22. [Epub ahead of print] PubMed PMID: 24850175.

5: Chen SM, Guo CL, Shi JJ, Xu YC, Chen Y, Shen YY, Su Y, Ding J, MengLH. HSP90 inhibitor AUY922 abrogates up-regulation of RTKs by mTORinhibitor AZD8055 and potentiates its antiproliferative activity inhuman breast cancer. Int J Cancer. 2014 Apr 7. doi: 10.1002/ijc.28880. [Epubahead of print] PubMed PMID: 24706460.

6: Zitzmann K, Ailer G, Vlotides G, Spoettl G, Maurer J, Göke B,Beuschlein F, Auernhammer CJ. Potent antitumor activity of the novelHSP90 inhibitors AUY922 and HSP990 in neuroendocrine carcinoid cells.Int J Oncol. 2013 Dec;43(6):1824-32. doi: 10.3892/ijo.2013.2130. Epub2013 Oct 4. PubMed PMID: 24100469; PubMed Central PMCID: PMC3834873.

7: Voruganti S, Lacroix JC, Rogers CN, Rogers J, Matts RL, Hartson SD.The anticancer drug AUY922 generates a proteomics fingerprint that ishighly conserved among structurally diverse Hsp90 inhibitors. J ProteomeRes. 2013 Aug 2;12(8):3697-706. doi: 10.1021/pr400321x. Epub 2013 Jun27. PubMed PMID: 23763277; PubMed Central PMCID: PMC3784992.

8: Sessa C, Shapiro GI, Bhalla KN, Britten C, Jacks KS, Mita M,Papadimitrakopoulou V, Pluard T, Samuel TA, Akimov M, Quadt C,Fernandez-Ibarra C, Lu H, Bailey S, Chica S, Banerji U. First-in-humanphase I dose-escalation study of the HSP90 inhibitor AUY922 in patientswith advanced solid tumors. Clin Cancer Res. 2013 Jul 1;19(13):3671-80.doi: 10.1158/1078-0432.CCR-12-3404. Epub 2013 Jun 11. PubMed PMID:23757357.

9: Garon EB, Finn RS, Hamidi H, Dering J, Pitts S, Kamranpour N, DesaiAJ, Hosmer W, Ide S, Avsar E, Jensen MR, Quadt C, Liu M, Dubinett SM,Slamon DJ. The HSP90 inhibitor NVP-AUY922 potently inhibits non-smallcell lung cancer growth. Mol Cancer Ther. 2013 Jun;12(6):890-900. doi:10.1158/1535-7163.MCT-12-0998. Epub 2013 Mar 14. PubMed PMID: 23493311;PubMed Central PMCID: PMC3681857.

10: Wainberg ZA, Anghel A, Rogers AM, Desai AJ, Kalous O, Conklin D,Ayala R, O"Brien NA, Quadt C, Akimov M, Slamon DJ, Finn RS. Inhibitionof HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-resistantbreast and gastric cancer. Mol Cancer Ther. 2013 Apr;12(4):509-19. doi:10.1158/1535-7163.MCT-12-0507. Epub 2013 Feb 8. PubMed PMID: 23395886.

11: Gandhi N, Wild AT, Chettiar ST, Aziz K, Kato Y, Gajula RP, WilliamsRD, Cades JA, Annadanam A, Song D, Zhang Y, Hales RK, Herman JM, ArmourE, DeWeese TL, Schaeffer EM, Tran PT. Novel Hsp90 inhibitor NVP-AUY922radiosensitizes prostate cancer cells. Cancer Biol Ther. 2013Apr;14(4):347-56. doi: 10.4161/cbt.23626. Epub 2013 Jan 28. PubMed PMID:23358469; PubMed Central PMCID: PMC3667875.

12: Walsby EJ, Lazenby M, Pepper CJ, Knapper S, Burnett AK. The HSP90inhibitor NVP-AUY922-AG inhibits the PI3K and IKK signalling pathwaysand synergizes with cytarabine in acute myeloid leukaemia cells. Br JHaematol. 2013 Apr;161(1):57-67. doi: 10.1111/bjh.12215. Epub 2013 Jan29. PubMed PMID: 23356405.

13: Hartmann S, Günther N, Biehl M, Katzer A, Kuger S, Worschech E,Sukhorukov VL, Krohne G, Zimmermann H, Flentje M, Djuzenova CS. Hsp90inhibition by NVP-AUY922 and NVP-BEP800 decreases migration and invasionof irradiated normoxic and hypoxic tumor cell lines. Cancer Lett. 2013May 1;331(2):200-10. doi: 10.1016/j.canlet.2012.12.027. Epub 2013 Jan20. PubMed PMID: 23340178.

14: Hsueh YS, Yen CC, Shih NY, Chiang NJ, Li CF, Chen LT. Autophagy isinvolved in endogenous and NVP-AUY922-induced KIT degradation ingastrointestinal stromal tumors. Autophagy. 2013 Feb 1;9(2):220-33. doi:10.4161/auto.22802. Epub 2012 Nov 29. PubMed PMID: 23196876; PubMedCentral PMCID: PMC3552885.

15: Armstrong H, Wolmarans A, Mercier R, Mai B, LaPointe P. Theco-chaperone Hch1 regulates Hsp90 function differently than itshomologue Aha1 and confers sensitivity to yeast to the Hsp90 inhibitorNVP-AUY922. PLoS One. 2012;7(11):e49322. doi:10.1371/journal.pone.0049322. Epub 2012 Nov 14. PubMed PMID: 23166640;PubMed Central PMCID: PMC3498168.

16: Niewidok N, Wack LJ, Schiessl S, Stingl L, Katzer A, Polat B,Sukhorukov VL, Flentje M, Djuzenova CS. Hsp90 Inhibitors NVP-AUY922 andNVP-BEP800 May Exert a Significant Radiosensitization on Tumor Cellsalong with a Cell Type-Specific Cytotoxicity. Transl Oncol. 2012Oct;5(5):356-69. Epub 2012 Oct 1. PubMed PMID: 23066444; PubMed CentralPMCID: PMC3470116.

17: Bao XH, Takaoka M, Hao HF, Fukazawa T, Yamatsuji T, Sakurama K,Takigawa N, Nakajima M, Fujiwara T, Naomoto Y. Antiproliferative effectof the HSP90 inhibitor NVP-AUY922 is determined by the expression ofPTEN in esophageal cancer. Oncol Rep. 2013 Jan;29(1):45-50. doi:10.3892/or.2012.2074. Epub 2012 Oct 9. PubMed PMID: 23064324.

18: Okui T, Shimo T, Fukazawa T, Mohammad Monsur Hassan N, Honami T,Ibaragi S, Takaoka M, Naomoto Y, Sasaki A. Novel HSP90 inhibitorNVP-AUY922 enhances the anti-tumor effect of temsirolimus against oralsquamous cell carcinoma. Curr Cancer Drug Targets. 2013Mar;13(3):289-99. PubMed PMID: 23016912.

19: Moser C, Lang SA, Hackl C, Wagner C, Scheiffert E, Schlitt HJ,Geissler EK, Stoeltzing O. Targeting HSP90 by the novel inhibitorNVP-AUY922 reduces growth and angiogenesis of pancreatic cancer.Anticancer Res. 2012 Jul;32(7):2551-61. PubMed PMID: 22753713.

20: Best OG, Mulligan SP. Heat shock protein-90 inhibitor, NVP-AUY922,is effective in combination with fludarabine against chronic lymphocyticleukemia cells cultured on CD40L-stromal layer and inhibits theiractivated/proliferative phenotype. Leuk Lymphoma. 2012Nov;53(11):2314-20. doi: 10.3109/10428194.2012.698278. Epub 2012 Jul 9.PubMed PMID: 22646928.