SNX-2112

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]
References:
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

Chitosan-functionalised single-walled carbon nanotube-mediated drug delivery of SNX-2112 in cancer cells.[Pubmed:27231263]

J Biomater Appl. 2016 Sep;31(3):379-86.

Delivery of amphiphobic drugs (insoluble in both water and oil) has been a great challenge in drug delivery. SNX-2112, a novel inhibitor of Hsp90, is a promising drug candidate for treating various types of cancers; however, the insolubility greatly limits its clinical application. This study aimed to build a new type of drug delivery system using single-walled carbon nanotubes (SWNTs) for controllable release of SNX-2112; chitosan (CHI) was non-covalently added to SWNTs to improve their biocompatibility. SWNTs-CHI demonstrated high drug-loading capability; the release of SNX-2112 was pH triggered and time related. The intracellular reactive oxygen species of SWNTs-CHI increased, compared with that of SWNTs, leading to higher mitogen-activated protein kinase and cell apoptosis. The results of western-blotting, lactate dehydrogenase (LDH) release assay, and cell viability assay analyses indicated that apoptosis-related proteins were abundantly expressed in K562 cells and that the drug delivery system significantly inhibited K562 cells. Thus, SWNT-CHI/SNX-2112 shows great potential as a drug delivery system for cancer therapy.

Elucidating the in vivo fate of nanocrystals using a physiologically based pharmacokinetic model: a case study with the anticancer agent SNX-2112.[Pubmed:25848269]

Int J Nanomedicine. 2015 Mar 31;10:2521-35.

INTRODUCTION: SNX-2112 is a promising anticancer agent but has poor solubility in both water and oil. In the study reported here, we aimed to develop a nanocrystal formulation for SNX-2112 and to determine the pharmacokinetic behaviors of the prepared nanocrystals. METHODS: Nanocrystals of SNX-2112 were prepared using the wet-media milling technique and characterized by particle size, differential scanning calorimetry, drug release, etc. Physiologically based pharmacokinetic (PBPK) modeling was undertaken to evaluate the drug's disposition in rats following administration of drug cosolvent or nanocrystals. RESULTS: The optimized SNX-2112 nanocrystals (with poloxamer 188 as the stabilizer) were 203 nm in size with a zeta potential of -11.6 mV. In addition, the nanocrystals showed a comparable release profile to the control (drug cosolvent). Further, the rat PBPK model incorporating the parameters of particulate uptake (into the liver and spleen) and of in vivo drug release was well fitted to the experimental data following administration of the drug nanocrystals. The results reveal that the nanocrystals rapidly released drug molecules in vivo, accounting for their cosolvent-like pharmacokinetic behaviors. Due to particulate uptake, drug accumulation in the liver and spleen was significant at the initial time points (within 1 hour). CONCLUSION: The nanocrystals should be a good choice for the systemic delivery of the poorly soluble drug SNX-2112. Also, our study contributes to an improved understanding of the in vivo fate of nanocrystals.

Effect of SNX-2112 on proliferation of esophageal cancer cells via regulation of excision repair cross-complementing 1, epidermal growth factor receptor, and p53 expression.[Pubmed:27420968]

Genet Mol Res. 2016 Jun 24;15(2). pii: gmr8318.

SNX-2112 is a potential molecular targeted therapeutic drug against esophageal cancer (EC). However, its exact mechanism of action remains to be explained. The aim of this study was to investigate the effect of SNX-2112 on excision repair cross- complementing 1 (ERCC1), epidermal growth factor receptor (EGFR), and p53, to elucidate the mechanism of action of SNX-2112 on EC. Fresh tumor sections were surgically obtained from 65 patients with EC, and the expression of ERCC1, EGFR, and p53 was determined by immunohistochemical staining. Furthermore, the effect of SNX-2112 (0.2 muM) on the proliferation of EC-9706 cells and the expression of ERCC1, EGFR, and p53 in these cells were analyzed by a cell proliferation assay and western blot, respectively. We observed a significant decrease and increase in ERCC1 (P = 0.001) and p53 (P = 0.043) expression, respectively, and no significant difference in EGFR (P = 0.59) expression, with the TNM stage of EC, which suggested that ERCC1 and p53 could be potential markers for the TNM stage of EC. We also observed a significant increase in ERCC1 expression, and decrease in p53 and EGFR expression, in EC-9706 cells treated with SNX-2112 (P < 0.05), indicating the regulation of EC by SNX-2112. Furthermore, SNX-2112 treatment induced a significant decrease in the proliferation of EC-9706, which confirmed the function of SNX- 2112. In summary, SNX-2112 inhibits the proliferation of EC cells by regulating the expression of ERCC1, EGFR, and p53.

Phospholipid-stabilized mesoporous carbon nanospheres as versatile carriers for systemic delivery of amphiphobic SNX-2112 (a Hsp90 inhibitor) with enhanced antitumor effect.[Pubmed:25936860]

Eur J Pharm Biopharm. 2015 Aug;94:30-41.

Systemic delivery of amphiphobic drugs (insoluble in both water and oil) represents a formidable challenge in drug delivery. This work aimed to engineer a functional mesoporous carbon material to efficiently load SNX-2112, an amphiphobic anticancer agent, and to evaluate its performance in tumor-targeting delivery. Hydrothermal reaction combined with high-temperature activation was used to fabricate glucose-based mesoporous carbon nanospheres (MCNs). SNX-2112-loaded MCNs stabilized by phospholipid (SN-PMCNs) were prepared by the absorption/solvent diffusion/high-pressure homogenization method. The obtained SN-PMCNs were 180nm around in particle size, showing a high drug load (42.7%) and acceptable physical stability. SN-PMCNs demonstrated an enhanced in vitro antitumor effect and increased uptake into cancer cells in comparison with the formulation of SNX-2112 solution (SN-Sol). The in vivo antitumor effect and biodistribution in 4T1 xenograft tumor mice, a breast cancer model, were also significantly improved through SN-PMCNs. It was shown that specific clathrin-dependent and nonspecific caveolae-dependent endocytosis were involved in the cellular trafficking of SN-PMCNs. Glucose transporter-mediated transport, prolonged body residence time and improved biodistribution via EPR effect were the main mechanisms of enhanced antitumor effect. SN-PMCNs have presented excellent tumor targeting properties and should be a promising carrier to address the systemic delivery of SNX-2112.

SNX-2112 (PF-04928473) selectively binds to the ATP pocket of HSP90α and HSP90β with Ka of 30 nM and 30 nM, uniformly more potent than 17-AAG.

SNX-2112,908112-43-6,Natural Products,HSP, buy SNX-2112 , SNX-2112 supplier , purchase SNX-2112 , SNX-2112 cost , SNX-2112 manufacturer , order SNX-2112 , high purity SNX-2112