Discovery of benzamide tetrahydro-4H-carbazol-4-ones as novel small molecule inhibitors of Hsp90

Barta, Thomas E.; Veal, James M.; Rice, John W.; Partridge, Jeffrey M.; Fadden, R. Patrick; Ma, Wei; Jenks, Matthew; Geng, Lifeng; Hanson, Gunnar J.; Huang, Kenneth H.; Barabasz, Amy; Foley, Briana; Otto, James C.; Hall, Steven E.

doi:10.1016/j.bmcl.2008.05.023

Cited by 84 publications

(50 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…38 Poloxamer 188 (P188) was obtained from BASF SE (Ludwigshafen, Germany). Polysorbate 80 (Tween ® 80) was obtained from Aladdin Reagent Co Ltd (Shanghai, People's Republic of China).…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

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

Dong

Wang

et al. 2015

IJN

View full text Add to dashboard Cite

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.

show abstract

“…38 Poloxamer 188 (P188) was obtained from BASF SE (Ludwigshafen, Germany). Polysorbate 80 (Tween ® 80) was obtained from Aladdin Reagent Co Ltd (Shanghai, People's Republic of China).…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

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

Dong

Wang

et al. 2015

IJN

View full text Add to dashboard Cite

show abstract

“…SNX-2112 was synthesized in our laboratory as previously described (17). Dimethylsulfoxide (DMSO), 4',6-diamidino-2-phenylindole (DAPI), and MTT were purchased from Sigma (St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

The heat shock protein 90 inhibitor SNX-2112 inhibits B16 melanoma cell growth in vitro and in vivo

et al. 2012

View full text Add to dashboard Cite

Abstract. SNX-2112 is a selective heat shock protein 90 (Hsp90) inhibitor which can exert a potent anticancer activity. In this study, we investigated the effects of SNX-2112 on B16 melanoma cells in vitro and in vivo. The 3-(4,5-dimetrylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis demonstrated that SNX-2112 dosedependently inhibited the growth of B16 cells, and induced G0/ G1 cell cycle arrest and apoptosis. Western blotting revealed that SNX-2112 lead to the degradation of Hsp90 client proteins including Akt, IKKα, NF-κB, B-Raf and GSK3β. Furthermore, we assessed the antitumor effect of SNX-2112 in vivo, using a xenograft model in C57BL/6 mice. Oral administration of SNX-2112 significantly inhibited the growth of B16 tumors in mice, with a 47% inhibition observed at dose of 80 mg/kg/day for 15 days, compared to control tumors. Hematoxylin-eosin (H&E) staining of xenograft tissues showed that SNX-2112 also inhibited angiogenesis and lead to a lower blood vessel density in the tumors, compared to the control group. These findings demonstrate that SNX-2112 can exhibit a potent anticancer activity against B16 melanoma cells both in vitro and in vivo, by inhibiting cell proliferation and inducing cell cycle arrest and apoptosis in a mechanism dependent on the degradation of Hsp90 client proteins. IntroductionHsp90 is an important ATP-dependent molecular chaperone required for protein folding, as well as the assembly and maintenance of the conformational stability of a diverse range of client proteins. Hsp90 client proteins play key roles in cellular metabolism, trafficking, signal transduction, chromatin remodeling, cell growth and differentiation (1-4). Hsp90 client proteins include cell survival and proliferation regulators, such as Akt, IKK, Raf, GSK3 and NF-κB (5-7). Hsp90 is overexpressed in tumor cells compared to their normal counterparts (8), and inhibition of Hsp90 has been considered as a possible strategy for the treatment of cancer.Currently, 14 drug candidates which target Hsp90 are undergoing clinical trials for multiple indications, either as single agents or in combination therapy, including 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504) and BIIB021 (9). 17-AAG was the first Hsp90 inhibitor to undergo phase III clinical trials, and is well tolerated and has a good therapeutic efficacy. However, 17-AAG has several potential limitations, including poor solubility, limited bioavailability and unsatisfactory hepatotoxicity (10-12). This has led to efforts to identify new, safer and more effective Hsp90 inhibitors for clinical applications.SNX-2112, a selective Hsp90 inhibitor, can bind to the N-terminal adenosine triphosphate binding site of Hsp90 and can exert significant growth inhibition of various cancer cell lines both in vitro and in vivo (13,14). In our previous research, SNX-2112 displayed promising anti-tumor activity in human chronic leukemia 16). In addition, SNX-2112 is ...

show abstract

“…However, therapeutic uses of 17-AAG is limited by the poor solubility and off-target toxicities [19,22]. As a result, enormous efforts have been directed at identifying the novel Hsp90 inhibitors with improved pharmacologic and toxicity profiles [23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

“…Expressed human CYP enzymes (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5) and pooled human liver microsomes (pHLM, n = 50) were purchased from BD Biosciences (Woburn, MA). BJ-B11 and its metabolite M1-1 (SNX-25a) with a purity of > 98% were synthesized in our laboratory as described previously [23,27]. b-Nicotinamide adenine dinucleotide 2¢-phosphate-reduced tetrasodium salt hydrate (NADPH), fenofibric acid, and digitonin were purchased from Sigma-Aldrich (St Louis, MO).…”

Section: Introductionmentioning

confidence: 99%

Metabolism elucidation of BJ-B11 (a heat shock protein 90 inhibitor) by human liver microsomes: identification of main contributing enzymes

Dong

Liu

et al. 2015

Expert Opinion on Drug Metabolism & Toxicology

View full text Add to dashboard Cite

show abstract

Discovery of benzamide tetrahydro-4H-carbazol-4-ones as novel small molecule inhibitors of Hsp90

Cited by 84 publications

References 30 publications

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

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

The heat shock protein 90 inhibitor SNX-2112 inhibits B16 melanoma cell growth in vitro and in vivo

Metabolism elucidation of BJ-B11 (a heat shock protein 90 inhibitor) by human liver microsomes: identification of main contributing enzymes

Contact Info

Product

Resources

About

Discovery of benzamide tetrahydro-4H-carbazol-4-ones as novel small molecule inhibitors of Hsp90

Cited by 84 publications

References 30 publications

Elucidating the in vivo fate of nanocrystals using a physiologically based pharmacokinetic model: a&nbsp;case study with the anticancer agent SNX-2112

Elucidating the in vivo fate of nanocrystals using a physiologically based pharmacokinetic model: a&nbsp;case study with the anticancer agent SNX-2112

The heat shock protein 90 inhibitor SNX-2112 inhibits B16 melanoma cell growth in vitro and in vivo

Metabolism elucidation of BJ-B11 (a heat shock protein 90 inhibitor) by human liver microsomes: identification of main contributing enzymes

Contact Info

Product

Resources

About

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

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