Luminespib

Luminespib (AUY-922, NVP-AUY922) is a highly potent HSP90 inhibitor for HSP90α/β with IC50 of 13 nM /21 nM in cell-free assays, weaker potency against the HSP90 family members GRP94 and TRAP-1, exhibits the tightest binding of any small-molecule HSP90 ligand. Phase 2.

NVP-AUY922 inhibits proliferation of various human cancer cell lines in vitro, with an average GI50 of 9 nM. The IC50 values of NVP-AUY922 fall in the range of 2 to 40 nM in these gastric cancer cell lines. IC50 value for the BEAS-2B cells is 28.49 nM. Treatment with NVP-AUY922 does not influence the expression of HSP90, but expression of HSP70 gets elevated by NVP-AUY922 treatment. NVP-AUY922 increases the binding of HSP70 to HSP90. NVP-AUY922 causes p23 dissociation from the HSP90 complex and can then recruit HSP70 to the HSP90 complex. After the treatment with NVP-AUY922, expression of receptor tyrosine kinases including VEGFR1, 2, 3 and PDGFRɑ is decreased. A decrease is also noticed in the expression of Akt and phospho-Akt. Meanwhile, treatment with NVP-AUY922 causes decreased expression of HER-2 in NCI-N87 cells. NVP-AUY922 treatment results in binding of HSP90 to client proteins and setting them up as targets for degradation by the proteasome. NVP-AUY922 can influence cell growth by affecting multiple signaling pathways. In addition, treatment with the proteasome inhibitor, MG132, restores expression of thymidylate synthase, which is decreased by NVP-AUY922. NVP-AUY922 increases the expression of cleaved caspase-3 leading to apoptosis in HSC-2 cells.

Treatment with NVP-AUY922 causes a robust antitumor response and inhibits p-Akt and VEGF expression in an HSC-2 xenograft model. In BT474, NVP-AUY922 shows complete loss of ERBB2 and substantial depletion of ERα, in addition to reductions in CDK4 and phospho-ERK1/2.

Hsp90 is a molecular chaperone of many different kinases, transcription factors, and hormone receptors involved in signal transduction, cell cycle regulation, and apoptosis. In addition to its important function in normal cell homeostasis, a high affinity form of Hsp90 is prevalent in tumor cells. Hsp90 inhibition has been associated with the degradation of oncogenic client proteins. NVP-AUY922 is a Hsp90 inhibitor (IC₅₀ = 21 nM in a FP binding assay) that prevents the proliferation of a range of human cancer cell lines in vitro with GI₅₀s averaging 9 nM. In a human colon cancer xenograft model, 50 mg/kg NVP-AUY922 inhibits tumor growth by ~50% compared to vehicle controls. Unlike some first generation Hsp90 inhibitors that are quickly glucuronidated, NVP-AUY922 is retained in tumors in vivo when administered at 4 mg/kg i.p. by cassette dosing in tumor-bearing mice.

NVP-AUY 922 is a potent inhibitor of heat shock protein 90 (Hsp90) that prevents the proliferation of a range of human cancer cell lines. NVP-AUY 922 has been shown to enhance the radiation sensitivity of tumor cell lines under hypoxia. Potent Hedgehog inhibitor.

ChEBI: A monocarboxylic acid amide obtained by formal condensation of the carboxy group of 5-(2,4-dihydroxy-5-isopropylphenyl)-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazole-3-carboxylic acid with the amino group of ethylamine.

HSP90α

HSP90α: 7.8 nM (IC₅₀); HSP90β: 21 nM (IC₅₀); GRP94: 535 nM (IC₅₀); TRAP-1: 85 nM (IC₅₀)

[1] PAUL A. BROUGH*. 4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer[J]. Journal of Medicinal Chemistry, 2007, 51 2: 196-218. DOI:10.1021/jm701018h
[2] SUZANNE A ECCLES. NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis.[J]. Cancer research, 2008: 2850-2860. DOI:10.1158/0008-5472.can-07-5256
[3] ANDREW J MASSEY. Preclinical antitumor activity of the orally available heat shock protein 90 inhibitor NVP-BEP800.[J]. Molecular Cancer Therapeutics, 2010: 906-919. DOI:10.1158/1535-7163.mct-10-0055
[4] KWON-HO SONG. HSP90A inhibition promotes anti-tumor immunity by reversing multi-modal resistance and stem-like property of immune-refractory tumors.[J]. Nature Communications, 2020: 562. DOI:10.1038/s41467-019-14259-y
[5] M. SCHWAB G M. A Low Membrane Hsp70 Expression in Tumor Cells With Impaired Lactate Metabolism Mediates Radiosensitization by NVP-AUY922[J]. Frontiers in Oncology, 2022. DOI:10.3389/fonc.2022.861266
[6] CHOLPON S DJUZENOVA. Hsp90 inhibitor NVP-AUY922 enhances radiation sensitivity of tumor cell lines under hypoxia.[J]. Cancer Biology & Therapy, 2012, 13 6: 425-434. DOI:10.4161/cbt.19294
[7] DANIELA SCHILLING . Sensitizing tumor cells to radiation by targeting the heat shock response[J]. Cancer letters, 2015, 360 2: Pages 294-301. DOI:10.1016/j.canlet.2015.02.033