PKI-179
目录号 : GC62140
A dual PI3K and mTOR inhibitor
Cas No.:1197160-28-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
PKI-179 is an orally bioavailable dual inhibitor of PI3K and mammalian target of rapamycin (mTOR).1 In an in vitro enzymatic assay, it potently inhibits PI3K (IC50s = 8, 24, 17, and 74 nM for isoforms α, β, δ, and γ, respectively), two common PI3Kα mutants, E545K and H1047R (IC50s = 14 and 11 nM, respectively), and mTOR (IC50 = 0.42 nM). PKI-179 is selective for PI3K and mTOR over a panel of 361 other kinases at IC50 values up to 50 μM, hERG (IC50 > 30 μM), and cytochrome P450 (CYP) isoforms (IC50s > 30 μM), but does have activity for CYP2C8 (IC50 = 3 μM). It inhibits proliferation through the Akt/mTOR signaling pathway in MDA-361 breast and PC3MM2 prostate cancer cell lines in vitro (IC50s = 22 and 29 nM, respectively) and inhibits tumor growth in an MDA-361 mouse xenograft model when used at a dose of 50 mg/kg.
1.Venkatesan, A.M., Chen, Z., dos Santos, O., et al.PKI-179: An orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitorBioorg. Med. Chem. Lett.20(19)5869-5873(2010)
| Cas No. | 1197160-28-3 | SDF | |
| 分子式 | C25H28N8O3 | 分子量 | 488.54 |
| 溶解度 | 储存条件 | Store at -20°C | |
| General tips | 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；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0469 mL | 10.2346 mL | 20.4692 mL |
| 5 mM | 0.4094 mL | 2.0469 mL | 4.0938 mL |
| 10 mM | 0.2047 mL | 1.0235 mL | 2.0469 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor
Bioorg Med Chem Lett 2010 Oct 1;20(19):5869-73.PMID:20797855DOI:10.1016/j.bmcl.2010.07.104.
A series of mono-morpholino 1,3,5-triazine derivatives (8a-8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed.
A structural insight into the inhibitory mechanism of an orally active PI3K/mTOR dual inhibitor, PKI-179 using computational approaches
J Mol Graph Model 2015 Nov;62:226-234.PMID:26500112DOI:10.1016/j.jmgm.2015.10.005.
The PI3K/AKT/mTOR signaling pathway has been identified as an important target for cancer therapy. Attempts are increasingly made to design the inhibitors against the key proteins of this pathway for anti-cancer therapy. The PI3K/mTOR dual inhibitors have proved more effective than the inhibitors against only single protein targets. Recently discovered PKI-179, an orally effective compound, is one such dual inhibitor targeting both PI3K and mTOR. This anti-cancer compound is efficacious both in vitro and in vivo. However, the binding mechanisms and the molecular interactions of PKI-179 with PI3K and mTOR are not yet available. The current study investigated the exact binding mode and the molecular interactions of PKI-179 with PI3Kγ and mTOR using molecular docking and (un)binding simulation analyses. The study identified PKI-179 interacting residues of both the proteins and their importance in binding was ranked by the loss in accessible surface area, number of molecular interactions of the residue, and consistent appearance of the residue in (un)binding simulation analysis. The key residues involved in binding of PKI-179 were Ala-805 in PI3Kγ and Ile-2163 in mTOR as they have lost maximum accessible surface area due to binding. In addition, the residues which played a role in binding of the drug but were away from the catalytic site were also identified using (un)binding simulation analyses. Finally, comparison of the interacting residues in the respective catalytic sites was done for the difference in the binding of the drug to the two proteins. Thus, the pairs of the residues falling at the similar location with respect to the docked drug were identified. The striking similarity in the interacting residues of the catalytic site explains the concomitant inhibition of both proteins by a number of inhibitors. In conclusion, the docking and (un)binding simulation analyses of dual inhibitor PKI-179 with PI3K and mTOR will provide a suitable multi-target model for studying drug-protein interactions and thus help in designing the novel drugs with higher potency.
Stereoselective synthesis of an active metabolite of the potent PI3 kinase inhibitor PKI-179
J Org Chem 2010 Mar 5;75(5):1643-51.PMID:20112997DOI:10.1021/jo9026269.
The synthesis and stereochemical determination of 1-(4-(4-((1R,5R,6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea (2), an active metabolite of the potent PI3 kinase inhibitor PKI-179 (1), is described. Stereospecific hydroboration of the double bond of 2,5-dihydro-1H-pyrrole 8 gave the 2,3-trans alcohol 9 exclusively. The configuration of the 3-hydroxyl group in 9 was inverted by an oxidation and stereoselective reduction sequence to give the corresponding 2,3-cis isomer 23. Both exo (21) and endo (27) isomers of the metabolite 2 were prepared via a practical synthetic route from 9 and 23, respectively, and the stereochemistry of 2 was determined to be endo. The endo isomer (27) was separated into two enantiomers 28 and 29 by chiral HPLC. Compound 2 was found to be enantiomerically pure and identical to the enantiomer 28. The absolute stereochemistry of the enantiomer 28 was determined by Mosher's method, thus establishing the stereochemistry of the active metabolite 2.
Turning down PI3K/AKT/mTOR signalling pathway by natural products: an in silico multi-target approach
SAR QSAR Environ Res 2023 Feb;34(2):163-182.PMID:36853097DOI:10.1080/1062936X.2023.2181392.
The PI3K/AKT/mTOR pathway is a significant target for cancer drug discovery. Many efforts have focused on discovering new inhibitors against key kinase proteins involved in this pathway for cancer treatment. PI3K/mTOR dual inhibitors, such as PKI-179, have been reported to be more effective than agents that act only on a single protein target. The present computational study aimed to discover triple target inhibitors against PI3K, AKT, and mTOR proteins. Accordingly, the PI3K protein bound with the ligand was used as input for e-pharmacophore modelling to generate the pharmacophore hypothesis and then screened for a library of 270,540 natural products from the Zinc database resulting in 57,220 compounds that matched the hypothesis. These compounds were then docked into the active site of PI3K, resulting in 292 compounds with better docking scores than the co-crystallized ligand. These compounds were re-docked into AKT and mTOR proteins. Besides, MM-GBSA binding free energy calculations, MD simulations, and ADMET prediction were carried out, leading to 5 potential triple-target inhibitors namely, ZINC000014644152, ZINC000014760695, ZINC000014644839, ZINC000095099451, and ZINC000005998557. In conclusion, these inhibitors may be possible leads for inhibiting PI3K/AKT/mTOR pathway, and they may be further evaluated in vitro and clinically as anticancer agents.