TAS-116-DataSheet-生命科学试剂-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemETAS-116Cat. No.: HY-15785CAS No.: 1260533-36-5分式: CHNO分量: 454.53作靶点: HSP作通路: Cell Cycle/DNA Damage; Metabolic Enzyme/Protease储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 125 mg/mL (275.0

2、1 mM; Need ultrasonic)Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 2.2001 mL 11.0004 mL 22.0007 mL5 mM 0.4400 mL 2.2001 mL 4.4001 mL10 mM 0.2200 mL 1.1000 mL 2.2001 mL请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存式和期限。体内实验 请根据您的实验动物和给药式选择适当的溶解案，配制前请先配制澄的储备液，再依次添加助溶剂(为保证实验结果的可靠性，体内实验的作液，建议您现现配，当天使；澄的储

3、备液可以根据储存条件，适当保存；以下溶剂前的百分指该溶剂在您配制终溶液中的体积占)：1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.08 mg/mL (4.58 mM); Clear solution2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.08 mg/mL (4.58 mM); Clear solution3. 请依序添加每种溶剂： 10% DMSO 90% corn oilSolubility: 2.08 mg/mL

4、 (4.58 mM); Clear solution1/3 Master of Small Molecules 您边的抑制剂师www.MedChemEBIOLOGICAL ACTIVITY物活性 TAS-116服物可利的，ATP 竞争性的，特异性的 HSP90/HSP90 抑制剂，Ki 值分别为 34.7 nM和 21.3 nM。不抑制其他 HSP90 家族蛋如 GRP94 1。TAS-116 具有较低的眼部毒性 2。IC50 & Target HSP90 HSP9034.7 nM (Ki) 21.3 nM (Ki)体外研究 TAS-116 binds not only to the conv

5、entional-binding pockets as existing Hsp-90 inhibitors, but also to a novel-binding pocket. Such a unique binding mode makes TAS-116 highly specific for Hsp-90/ without inhibitingother Hsp-90 family proteins such as GRP94 in endoplasmic reticulum or TRAP-1 in mitochondria 3.TAS-116 (0-5 M, 48 hours)

6、 inhibits human retinal pigment epithelial ARPE-19 cell lines and NCI-H929 MMcells growth 2.More significant degradation of p-C-Raf and p-MEK1/2, HSP90 client proteins and key RAS/RAF/MEKpathway regulators, is triggered by TAS-116 (0.125-1 M, 24 hours) than 17-AAG in INA6 and NCI-H929 MMcells 2.Cell

7、 Viability Assay 2Cell Line: Human retinal pigment epithelial ARPE-19 cell lines and NCI-H929 MM cellsConcentration: 0-5 MIncubation Time: 48 hoursResult: Inhibited NCI-H929 MM cells growth with an IC50 of 0.35 M.Western Blot Analysis 2Cell Line: MM cell lines INA6 and NCI-H929 cellsConcentration: 0

8、.125-1 MIncubation Time: 24 hoursResult: Targeted potently HSP90 client proteins including C-Raf and MEK1/2; as well asinhibited upregulation of HSP27 and overcomes 17-AAG resistance mechanisms.体内研究TAS-116 (12.0 mg/kg, p.o., 14 days) shows antitumor activity without inducing eye injury in rats. TAS-

9、116 isdistributed less in retina than in plasma in rats; consequently, TAS-116 does not produce any detectablephotoreceptor injury 1. TAS-116 triggers enhanced in vivo anti-MM activities, both alone and in combinationwith Bortezomib (BTZ), with a favorable safety profile. Mice treated with TAS-116 (

10、10 mg/kg and 15 mg/kg,orally, 38 days), BTZ, or TAS-116 plus BTZ show significantly enhance growth inhibition versus the vehiclecontrol group. Median overall survival of treated animals (TAS-116, orally, 10 mg/kg=33 days, 15 mg/kg=37days, BTZ=36 days, and the combination=56.5 days) is significantly

11、longer than vehicle control 2.The favorable pharmacokinetic profile of TAS-116 is reflected in its dose-dependent antitumor activity; the2/3 Master of Small Molecules 您边的抑制剂师www.MedChemET/C (tumor volume of TAS-116-treated mice vs. vehicle-treated mice) is 47%, 21%, and 9% for doses of 3.6mg/kg, 7.1

12、 mg/kg, and 14.0 mg/kg, respectively. TAS-116 is orally absorbed and has a bioavailability ofalmost 100% in mice, and 69.0% in rats. TAS-116 has moderate terminal elimination half-life (t1/2=8.2 h, 2.5h, 4.4 h and 2.2 h for mouse (3.6 mg/kg, p.o.), mouse (7.1 mg/kg, p.o.), mouse (14.0 mg/kg, p.o.),

13、rat (4mg/kg, p.o.). TAS-116 is more rapidly eliminated from retina (t1/2=3.4 hours) than the other HSP90 inhibitors(t1/2=7.1-19.1 hours) 1.Animal Model: Male F344 nude rats (6 weeks old) with established NCI-H1975 xenografts (6 weeks old)1Dosage: 12.0 mg/kgAdministration: Oral administration; daily;

14、 two weeksResult: Led to tumor shrinkage. Showed antitumor activity without inducing eye injury in rats anddid not cause ocular toxicity at the effective dose in the NCI-H1975 rat xenograft model.Animal Model: CB17 SCID mice (48-54 days old) with murine xenograft model 2Dosage: 10 and 15 mg/kgAdmini

15、stration: Oral administration; 5 days a week; for 28 daysResult: Enhanced significantly growth inhibition versus the vehicle control group. The delay intumor growth was greater in the combination-treated group compared with eithermonotherapy cohort.Animal Model: Mice, Rats, and Dogs 1Dosage: 3.0 mg/

16、kg for dogs, 4.0 mg/kg for rats, 3.6, 7.1 and 14.0 mg/kg for miceAdministration: Oral administration; daily; 20 daysResult: Absorbed orally and had a bioavailability of almost 100% in mice, 69.0% in rats, and73.9% in dogs without special formulation.REFERENCES1. Ohkubo S, et al. TAS-116, a highly se

17、lective inhibitor of heat shock protein 90 and , demonstrates potent antitumor activity andminimal ocular toxicity in preclinical models. Mol Cancer Ther. 2015 Jan;14(1):14-22.2. Suzuki R, et al. Anti-tumor activities of selective HSP90/ inhibitor, TAS-116, in combination with bortezomib in multiple myeloma.Leukemia. 2015 Feb;29(2):510-4.3. Utsugi T. New challenges and inspired answers for anticancer drug discovery and development. Jpn J Clin Oncol. 2013 Oct