SNX-2112 is a potent inhibitor of synthetic heat shock protein (Hsp 90) with IC50 value of 30 nM.[1]
HSP90 (heat shock proteins) is widely expressed as a molecular chaperone. It plays an important role in the folding and stabilization of cellular proteins. HSP90 protects client proteins from degradation and maintains them in an active conformation. Many clientsof HSP90 are transcription factors or protein kinases such as: Bcr-Abl, tyrosine kinas, EGFR family members, IGF1-R, c-Met, steroid hormone receptors, p53, Mdm2 and telomerase. In a variety of cancers, overexpressed hsp90 has been detected. Hsp90 also play an important role in maintaining the transformed phenotype of cancer cell. So, Hsp 90 is one attractive target for cancer therapy.
SNX-2112 is a potent inhibitor of Hsp 90 in different cancer cell lines. In the MTT assay, SNX-2112 inhibited A-375 cells with IC50 values of 1.25 μM at 48h. In the western blot assay, 0.2 M SNX-2112 significantly reduced several growth-related Hsp90 client proteins such as Akt, p-Akt, IKKα, B-Raf, Erk1/2, p-Erk1/1, GSK3β and Chk1 in a time-dependent manner after 24h treatment. In the DAPI staining and the TUNEL assay, conclusive double-stranded DNA fragmentation were produced after exposure to 0.2?μM SNX-2112.[2] Moreover, in the cell cycle assays, in 3 MET-amplified tumor cell lines (GTL-16, MKN-45 and EBC-1), 50nM SNX-2112 induced G1 arrest while in higher concentration such as 100 and 1000nM, more cells accumulated in G2 phase.[3] In pediatric cancer cell lines (SK-N-DZ, SK-N-AS, BE(2)-C, Saos-2, SK-N-SH, and U-2-OS ) SNX-2112 showed inhibition properties? at IC50 values ranging from 20-40 nM.[4]
参考文献:
1.Chandarlapaty S, et al.SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers. Clin cancer Res(2008) 14(1): 240-248
2.Kai-Sheng Liu, et al. SNX-2112, an Hsp90 inhibitor, induces apoptosis and autophagy via degradation of Hsp90 client proteins in human melanoma A-375 cells. Cancer Letters. (2012) 318 180–188
3.Antitumor activity of SNX-2112, a synthetic heat shock protein-90 inhibitor, in MET-amplified tumor cells with or without resistance to selective MET inhibition. Clin Cancer Res. (2011) 17(1): 122–133
4.Daniel le C. Chin n,BS, et al. Anti-Tumor Activity of the HSP90 Inhibitor SNX-2112 in Pediatric Cancer Cell Lines. Pediatr Blood Cancer (2012)58:885–890
| Cell experiment [1-3]: | |
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Cell lines |
nu/nu athymic BALB/c female mice |
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Preparation method |
The solubility of this compound in DMSO is > 23.05 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
IC50: 10-50 nmol/L |
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Applications |
Treatment of BT-474 cells with 1 μmol/L SNX-2112 resulted in down-regulation of HER2 expression within 3 to 6 h of drug exposure with near-complete loss of HER2 expression by 10 h. SNX-2112 induced Hsp90 client degradation, inhibited Erk and Akt activation, and induced apoptosis in HER2-overexpressing cells. In a panel of breast, lung, and ovarian cancer cell lines, SNX-2112 inhibited cell proliferation with IC50 values ranging from 10 to 50 nmol/L. In BT-474 cells (HER2 amplified, breast cancer), the antiproliferative effect of SNX-2112 was associated with hypophosphorylation of Rb, arrest in G1, and modest levels of apoptosis. SNX-2112 induced autophagy in a time- and dose-dependent manner via Akt/mTOR/p70S6K inhibition. SNX-2112 induced significant apoptosis and autophagy in human melanoma A-375 cells. SNX-2112 (72 h) induced apoptosis in human chronic leukemia K562 cells with the IC50 of 0.92 μM. |
| Animal experiment [3]: | |
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Animal models |
K562-NOD/SCID mice |
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Dosage form |
6 mg/kg, tail vain injection from days 5–9 and days 12–16 |
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Application |
SNX-2112 showed therapeutic effect on NOD/SCID mice inoculated with K562 cells. SNX-2112 treatment prolonged survival of NOD/SCID mice inoculated with K562 cells. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Chandarlapaty S, Sawai A, Ye Q, et al. SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase–dependent cancers[J]. Clinical Cancer Research, 2008, 14(1): 240-248. [2]. Liu K S, Liu H, Qi J H, et al. SNX-2112, an Hsp90 inhibitor, induces apoptosis and autophagy via degradation of Hsp90 client proteins in human melanoma A-375 cells[J]. Cancer letters, 2012, 318(2): 180-188. [3]. Jin L, Xiao C L, Lu C H, et al. Transcriptomic and proteomic approach to studying SNX‐2112‐induced K562 cells apoptosis and anti‐leukemia activity in K562‐NOD/SCID mice[J]. FEBS letters, 2009, 583(12): 1859-1866. | |
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