PDK1 inhibitorPDK1 inhibitor CAS# 1001409-50-2 |
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Quality Control & MSDS
3D structure
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| Cas No. | 1001409-50-2 | SDF | Download SDF |
| PubChem ID | 49766501 | Appearance | Powder |
| Formula | C28H22F2N4O4 | M.Wt | 516.5 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 100 mg/mL (193.61 mM) H2O : < 0.1 mg/mL (insoluble) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 1-[(3,4-difluorophenyl)methyl]-2-oxo-N-[(1R)-2-[(2-oxo-1,3-dihydrobenzimidazol-5-yl)oxy]-1-phenylethyl]pyridine-3-carboxamide | ||
| SMILES | C1=CC=C(C=C1)C(COC2=CC3=C(C=C2)NC(=O)N3)NC(=O)C4=CC=CN(C4=O)CC5=CC(=C(C=C5)F)F | ||
| Standard InChIKey | GCWCGSPBENFEPE-VWLOTQADSA-N | ||
| Standard InChI | InChI=1S/C28H22F2N4O4/c29-21-10-8-17(13-22(21)30)15-34-12-4-7-20(27(34)36)26(35)31-25(18-5-2-1-3-6-18)16-38-19-9-11-23-24(14-19)33-28(37)32-23/h1-14,25H,15-16H2,(H,31,35)(H2,32,33,37)/t25-/m0/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | PDK1 inhibitor is a potent and selective inhibitor of PDK1 with potential as anticancer agent. | |||||
| Targets | PDK1 | |||||
PDK1 inhibitor Dilution Calculator
PDK1 inhibitor Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.9361 mL | 9.6805 mL | 19.3611 mL | 38.7222 mL | 48.4027 mL |
| 5 mM | 0.3872 mL | 1.9361 mL | 3.8722 mL | 7.7444 mL | 9.6805 mL |
| 10 mM | 0.1936 mL | 0.9681 mL | 1.9361 mL | 3.8722 mL | 4.8403 mL |
| 50 mM | 0.0387 mL | 0.1936 mL | 0.3872 mL | 0.7744 mL | 0.9681 mL |
| 100 mM | 0.0194 mL | 0.0968 mL | 0.1936 mL | 0.3872 mL | 0.484 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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PDK1 inhibitor is an potent and selective inhibitor of PDK1 with potential as anticancer agent. GSK 2334470,a inhibitor of PDK1, has IC50 value of 0.00251µM and CHEMBL1172241 with IC50 value of 0.085µM. [1]
PDPK1 stands for 3-phosphoinositide-dependent protein kinase 1, which is crucial for the activation of AKT/PKB and many other AGC kinases including PKC, S6K, SGK. [2]An important role for PDPK1 is in the signalling pathways activated by several growth factors and hormones including insulin signaling. PDPK1 functions downstream of PI3K through PDPK1's interaction with membrane phospholipids.[3]PI3K indirectly regulates PDPK1 by phosphorylating phosphatidylinositols which in turn generates phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. [4]However, PDPK1 is believed to be constitutively active and does not always require phosphatidylinositols for its activities. Phosphatidylinositols are only required for the activation at the membrane of some substrates including AKT. PDPK1 however does not require membrane lipid binding for the efficient phosphorylation of most of its substrates in the cytosol.PDK1 is implicated in the development and progression of melanomas.[5]Many cancer-driving mutations induce activation of PDK1 targets including Akt, S6K (p70 ribosomalS6 kinase) and SGK (serum- and glucocorticoid-induced protein kinase).
GSK2334470 is more effective at inhibiting PDK1 substrates that are activated in the cytosol rather than at the plasma membrane. Consistent with this, GSK2334470 inhibited Akt activation in knock-in embryonic stem cells expressing a mutant of PDK1 that is unable to interact with phosphoinositides more potently than in wild-type cells by Immunoblotting.[6]GSK2334470 also suppressed T-loop phosphorylation and activation of RSK2 (p90 ribosomal S6 kinase 2), another PDK1 target activated by the ERK(extracellular-signal-regulated kinase) pathway.[7] GSK2334470 will be useful in probing biological processes controlled by PDK1. Therefore, GSK2334470 is much more specific than other reported PDK1 inhibitors.
Reference:
1.MurphyST. et al. Discovery of novel, potent, and selective inhibitors of 3-phosphoinositide-dependent kinase (PDK1). J Med Chem. 2011, 54(24):8490-500.
2.Mora A, Komander D, van Aalten DM, Alessi DR. "PDK1, the master regulator of AGC kinase signal transduction". Semin. Cell Dev. Biol. 2004,15 (2): 161-70.
3.Vanhaesebroeck B, Alessi DR. "The PI3K-PDK1 connection: more than just a road to PKB". Biochem. J. 2000, 346 (3): 561-76.
4.Frödin M, Antal TL. Et al. "A phosphoserine/threonine-binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation". EMBO J. 2002, 21 (20): 5396-407.
5.Scortegagna, M.. et al. "Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of BrafV600E::Pten-/- melanoma". Oncogene.2013.
6.Ayaz NAJAFOV. Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1. Biochem. J. (2011) 433, 357-369 .
7.Tamguney, T. et al. Analysis of 3-phosphoinositide-dependent kinase-1 signaling and function in ES cells. Cell ,2008, 314, 2299–2312.
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Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery.[Pubmed:21459573]
Bioorg Med Chem Lett. 2011 May 15;21(10):3078-83.
We report the use of a fragment-based lead discovery method, Tethering with extenders, to discover a pyridinone fragment that binds in an adaptive site of the protein PDK1. With subsequent medicinal chemistry, this led to the discovery of a potent and highly selective inhibitor of PDK1, which binds in the 'DFG-out' conformation.
A Small Molecule Inhibitor of PDK1/PLCgamma1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion.[Pubmed:27199173]
Sci Rep. 2016 May 20;6:26142.
Strong evidence suggests that phospholipase Cgamma1 (PLCgamma1) is a suitable target to counteract tumourigenesis and metastasis dissemination. We recently identified a novel signalling pathway required for PLCgamma1 activation which involves formation of a protein complex with 3-phosphoinositide-dependent protein kinase 1 (PDK1). In an effort to define novel strategies to inhibit PLCgamma1-dependent signals we tested here whether a newly identified and highly specific PDK1 inhibitor, 2-O-benzyl-myo-inositol 1,3,4,5,6-pentakisphosphate (2-O-Bn-InsP5), could affect PDK1/PLCgamma1 interaction and impair PLCgamma1-dependent cellular functions in cancer cells. Here, we demonstrate that 2-O-Bn-InsP5 interacts specifically with the pleckstrin homology domain of PDK1 and impairs formation of a PDK1/PLCgamma1 complex. 2-O-Bn-InsP5 is able to inhibit the epidermal growth factor-induced PLCgamma1 phosphorylation and activity, ultimately resulting in impaired cancer cell migration and invasion. Importantly, we report that 2-O-Bn-InsP5 inhibits cancer cell dissemination in zebrafish xenotransplants. This work demonstrates that the PDK1/PLCgamma1 complex is a potential therapeutic target to prevent metastasis and it identifies 2-O-Bn-InsP5 as a leading compound for development of anti-metastatic drugs.
Nanoparticle delivery of an AKT/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer.[Pubmed:25516710]
Int J Nanomedicine. 2014 Dec 3;9:5653-65.
The K-ras mutation in pancreatic cancer can inhibit drug delivery and increase drug resistance. This is exemplified by the therapeutic effect of PH-427, a small molecule inhibitor of AKT/PDK1, which has shown a good therapeutic effect against a BxPC3 pancreatic cancer model that has K-ras, but has a poor therapeutic effect against a MiaPaCa-2 pancreatic cancer model with mutant K-ras. To increase the therapeutic effect of PH-427 against the MiaPaCa-2 pancreatic cancer model with mutant K-ras, we encapsulated PH-427 into poly(lactic-co-glycolic acid) nanoparticles (PNP) to form drug-loaded PH-427-PNP. PH-427 showed a biphasic release from PH-427-PNP over 30 days during studies in sodium phosphate buffer, and in vitro studies revealed that the PNP was rapidly internalized into MiaPaCa-2 tumor cells, suggesting that PNP can improve PH-427 delivery into cells harboring mutant K-ras. In vivo studies of an orthotopic MiaPaCa-2 pancreatic cancer model showed reduced tumor load with PH-427-PNP as compared with treatment using PH-427 alone or with no treatment. Ex vivo studies confirmed the in vivo results, suggesting that PNP can improve drug delivery to pancreatic cancer harboring mutant K-ras.
Improved Treatment of Pancreatic Cancer With Drug Delivery Nanoparticles Loaded With a Novel AKT/PDK1 Inhibitor.[Pubmed:26918875]
Pancreas. 2016 Sep;45(8):1158-66.
OBJECTIVES: This research study sought to improve the treatment of pancreatic cancer by improving the drug delivery of a promising AKT/PDK1 inhibitor, PHT-427, in poly(lactic-co-glycolic) acid (PLGA) nanoparticles. METHODS: PHT-427 was encapsulated in single-emulsion and double-emulsion PLGA nanoparticles (SE-PLGA-427 and DE-PLGA-427). The drug release rate was evaluated to assess the effect of the second PLGA layer of DE-PLGA-427. Ex vivo cryo-imaging and drug extraction from ex vivo organs was used to assess the whole-body biodistribution in an orthotopic model of MIA PaCa-2 pancreatic cancer. Anatomical magnetic resonance imaging (MRI) was used to noninvasively assess the effects of 4 weeks of nanoparticle drug treatment on tumor size, and diffusion-weighted MRI longitudinally assessed changes in tumor cellularity. RESULTS: DE-PLGA-427 showed delayed drug release and longer drug retention in the pancreas relative to SE-PLGA-427. Diffusion-weighted MRI indicated a consistent decrease in cellularity during drug treatment with both types of drug-loaded nanoparticles. Both SE- and DE-PLGA-427 showed a 6-fold and 4-fold reduction in tumor volume relative to untreated tumors and an elimination of primary pancreatic tumor in 68% of the mice. CONCLUSIONS: These results indicated that the PLGA nanoparticles improved drug delivery of PHT-427 to pancreatic tumors, which improved the treatment of MIA PaCa-2 pancreatic cancer.
