A selective inhibitor of Hsp90
AT13387, discovered by a high-throughput x-ray craystallography fragment-based platform, is a non-geldanamycin heat shock proterin 90 (HPS90), a molecule chaperone regulating signal transduction pathways for cell growth and survival, inhibitor reportedly resulting in client protein degradation, suppression of signaling, and inducing cell cycle arrest and apoptosis. Since structurally unrelated to geldanamycin, it has high affinity for binding HSP90 (Kd = 0.5nM) and exhibited an in vitro cytotoxicity showing a median EC50 value of 41 nM. A long tumor-specific retention was observed in AT13387 during xenograft studies, which indicated the possibility of less frequent dosing. However, preliminary results showed that the antitumor activity of AT13387 against solid tumor and leukemia models is similar to alvespimycin.
Reference
?[1].Min H. Kang, C. Patrick Reynolds, Peter J. Houghton, Denise Alexander, Christopher L. Morton, E. Anders Kolb, Richard Gorlick, Stephen T. Keir, Hernan Carol, Richard Lock, John M. Maris, Amy Wozniak, and Malcolm A. Smith. Initial Testing (Stage 1) of AT13387, an HSP90 Inhibitor, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2012; 59(1): 185-188
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Cell experiment: |
In vitro testing is performed using DIMSCAN. Cells are incubated in the presence of Onalespib for 96 hours at concentrations from 1 nM to 10 μM[2]. |
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Animal experiment: |
HCT116 cells are injected SC into the right hind flank of male nude BALB/c mice. Tumours are apparent 7 to 10 days later. Mice are arranged into matched groups of 12 according to tumour volume giving a group mean of approximately 100 mm[3] at initiation of dosing. Tumour volumes are measured every 2 days. Statistical significance between groups is assessed using nonparametric one-way ANOVA. Mice are given the lactate salt of Onalespib using a repeated cycle of dosing of once per day for three days, no dose for three days, once per day for three days etc., for four dosing cycles at 60 mg/kg/dose (as free base equivalents) dissolved in 17.5% hydroxypropyl-β-cyclodextrin via the IP route. Control mice receive dose vehicle only via the same route. Tolerability is assessed by recording body weight, clinical observations and survival[1]. |
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参考文献: [1]. Woodhead AJ, et al. Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. J Med Chem. 2010 Aug 26;53(16):5956-69. |
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