Bimiralisib-PQR309-DataSheet-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEBimiralisibCat. No.: HY-12868CAS No.: 1225037-39-7Synonyms: PQR309分式: CHFNO分量: 411.38作靶點: PI3K; mTOR作通路: PI3K/Akt/mTOR儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 50 mg/mL (121.54 mM)* m

2、eans soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 2.4308 mL 12.1542 mL 24.3084 mL5 mM 0.4862 mL 2.4308 mL 4.8617 mL10 mM 0.2431 mL 1.2154 mL 2.4308 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲備液，并請注意儲備液的保存式和期限。體內(nèi)實驗請根據(jù)您的實驗動物和給藥式選擇適當(dāng)?shù)娜芙獍?，配制前請先配制澄清的儲備液，再依次添加助溶?為保證實驗結(jié)果的可靠性，體內(nèi)實驗的作液

3、，建議您現(xiàn)現(xiàn)配，當(dāng)天使；澄清的儲備液可以根據(jù)儲存條件，適當(dāng)保存；以下溶劑前的百分 指該溶劑在您配制終溶液中的體積占)：1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (6.08 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (6.08 mM); Clear solution1/3 Master of Small Molecules 您邊的抑制劑師www.M

4、edChemE3. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (6.08 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Bimiralisib (PQR309)種有效的，可滲透腦的，PI3K/mTOR 抑制劑，抑制 PI3K, PI3K, PI3K, PI3K和 mTOR，IC50 分別為 33 nM，451 nM，661 nM，708 nM 和 89 nM。Bimiralisib是mTORC1 和 mTORC2抑制劑。IC50 & Target PI3K PI3K PI3K PI3K33

5、nM (IC50) 661 nM (IC50) 451 nM (IC50) 708 nM (IC50)PI3K-H1047R PI3K-E545K PI3K-E542K Vps3436 nM (IC50) 136 nM (IC50) 63 nM (IC50) 6486 nM (IC50)mTOR mTORC1 mTORC2 DNA-PK89 nM (IC50) 8567 nM (IC50)體外研究 Bimiralisib is a highly selective pan-PI3K inhibitor with a balanced targeting of mTOR kinase. Bimi

6、ralisib alsoinhibits PI3K-H1047R), PI3K-E542K and PI3K-E545K with IC50s of 36 nM, 63 nM and 136 nM,respectively 1.體內(nèi)研究 Oral administration yields similar concentrations of Bimiralisib in brain and plasma samples illustrates thatBimiralisib readily passes the bloodbrain barrier. In mice, both po and

7、iv application routes show a rapiddrop below 200 ng/mL (0.5 M) of PQR309 within 50 determined in tumor cell lines. In female rats a singleoral dose (10 mg/kg) achieves similar drug levels as a single intravenous injection (5 mg/kg) with regard toCmax. The half-life of 5-8 h and an AUC0.25-12 of arou

8、nd 14 000 hng/mL contributed to an excellent oralbioavailability of PQR309 (50%). Twenty-four hours after po administration, plasma levels of PQR309 arestill 2 M (800-1000 ng/mL). Moreover, after 1-2 h exposure to PQR309 , drug levels in rat brain samplesare comparable to plasma levels, confirming r

9、apid access of PQR309 to the brain 1.PROTOCOLCell Assay 1 Human tumor cell lines are seeded into 96-well microtiter plates and exposed to five (1/2 log serial) drugdilutions plus control, followed by 48 h (except for two controls of each cell line which are fixed with TCA (cellpopulation at t =0 h T

10、z). The assay is terminated by fixation with TCA (10% final). Cell density is determinedusing a sulforhodamine B staining protocol and the absorbance measured at 515 nm. Using sevenabsorbance measurements, the percentage growth is calculated at each of the drug concentrations levels.Percentage growt

11、h inhibition is calculated. The NTRC Oncolines 44 cell lines are exposed for 72 h to 9-point3-fold serial dilutions of Bimiralisib. The concentration of 50% growth inhibition is associated with the signal(luminescenceuntreated,t=72h-luminescencet=0)/2)+luminescencet=0. The data set integrated here i

12、s usedfor IC50 calculations. IC50 values of A2058 or SKOV3 cell proliferation given are determined and calculated1.2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEMCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 1Administration 1 Healthy mal

13、e nude NIH rats are used. 2107 PC-3 cells are injected subcutaneously at day 0 (D0) in 200 Lof RPMI1640 into the right flank of male nude rats, 24 h after a whole-body irradiation with a -source (5 Gy,60Co). Tumor-bearing rats are randomized on day 16 (mean volume of 33070 mm3 according to theirindi

14、vidual tumor volume into five groups of each eight animals using Vivo manager software. Analysis ofvariance is performed to test for homogeneity between groups. Daily administration on D17-D44 and fromD51 to D57: group 1, vehicle; group 2, compound 1 at 5 mg/kg; group 3, Bimiralisib at 10 mg/kg. Gro

15、up 4:Bimiralisib at 15 mg/kg from D17 to D21, from D24 to D28, from D34 to D38, from D41 to D4, and from D51to D56. Group 5: one iv injection of Vinorelbine at 2.5 mg/kg on D17, D24, D31, and D38. Final termination ofrats is performed on D87. Body weight is measured at least twice a week. Length and

16、 width of tumors aremeasured and recorded twice a week with calipers, and the tumor volume is estimated.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Beaufils F, et al. 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-

17、amine (PQR309), a Potent, Brain-Penetrant, OrallyBioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology. J Med Chem. 2017 Sep 14;60(17):7524-7538.2. Wicki A, et al. First-in human, phase 1, dose-escalation pharmacokinetic and pharmacodynamic study of the oral dual PI3K andmTORC1/2 inhibitor PQR309 in patients with advanced