PND-1186Potent FAK inhibitor CAS# 1061353-68-1 |
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Quality Control & MSDS
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| Cas No. | 1061353-68-1 | SDF | Download SDF |
| PubChem ID | 25073775 | Appearance | Powder |
| Formula | C25H26F3N5O3 | M.Wt | 501.5 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | SR-2516; VS-4718 | ||
| Solubility | DMSO : ≥ 34 mg/mL (67.80 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 2-[[2-(2-methoxy-4-morpholin-4-ylanilino)-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide | ||
| SMILES | CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)NC3=C(C=C(C=C3)N4CCOCC4)OC | ||
| Standard InChIKey | IGUBBWJDMLCRIK-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C25H26F3N5O3/c1-29-24(34)17-5-3-4-6-19(17)31-21-14-23(30-15-18(21)25(26,27)28)32-20-8-7-16(13-22(20)35-2)33-9-11-36-12-10-33/h3-8,13-15H,9-12H2,1-2H3,(H,29,34)(H2,30,31,32) | ||
| 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 | PND-1186 is a potent inhibitor of focal adhesion kinase (FAK) with IC50 value of 1.5 nM. | |||||
| Targets | FAK | |||||
| IC50 | 1.5 nM | |||||
PND-1186 Dilution Calculator
PND-1186 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.994 mL | 9.9701 mL | 19.9402 mL | 39.8804 mL | 49.8504 mL |
| 5 mM | 0.3988 mL | 1.994 mL | 3.988 mL | 7.9761 mL | 9.9701 mL |
| 10 mM | 0.1994 mL | 0.997 mL | 1.994 mL | 3.988 mL | 4.985 mL |
| 50 mM | 0.0399 mL | 0.1994 mL | 0.3988 mL | 0.7976 mL | 0.997 mL |
| 100 mM | 0.0199 mL | 0.0997 mL | 0.1994 mL | 0.3988 mL | 0.4985 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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PND-1186 is a reversible inhibitor of FAK (focal adhesion kinase) with IC50 value of 1.5 nM [1].
The cytoplasmic protein-tyrosine kinase FAK is associated with integrins and growth factor receptors. It modulates a variety of cellular processes when it is activated. Since the elevated expression of FAK is found in many tumors, the inhibitors of FAK are developed as anti-tumor drugs in cancer therapy. PND-1186 is one of these ATP-competitive small-molecule inhibitors. It inhibited the autophosphorylation of FAK tyrosine-397 with IC50 value of 0.1 μM in breast carcinoma cells. When the concentration was up to 1 μM, PND-1186 also inhibited more than 50% of the activities of other kinases, such as CDK2, Lck, Aurora-A and ACK1 [1].
PND-1186 at concentrations of 0.1 to 1 μM inhibited the phosphorylation of FAK Tyr-397 and increased the protein level of FAK in murine breast carcinoma 4T1 cells, ID8 ovarian carcinoma cells and human MD-MBA-231 cells. Meanwhile, PND-1186 significantly induced cell apoptosis and increased the cleavage caspase 3 in suspended but not adherent 4T1 cells. Besides that, PND-1186 is found to inhibit the movement of 4T1 cells in both the wound healing assays and the millicell chamber motility assays. Treatment of PND-1186 at 0.4 μM for 4 hours showed the maximal inhibition of about 60%. In HEY ovarian cancer cells, treatment of PND-1186 caused the decrease of pY397 FAK, β5 integrin and osteopontin. It also induced cell cycle arrest at G0-G1 phase [1, 2].
In subcutaneous 4T1 tumors, administration of PND-1186 at dose of 100 mg/kg caused inhibition of both FAK Tyr-397 phosphorylation and p130Cas Tyr-410 phosphorylation. In orthotopic 4T1 tumors, administration of 150 mg/kg PND-1186 for 16 days finally reduced 3.1-fold tumor volume. Moreover, PND-1186 is reported to have anti-inflammatory effects and can suppress the processes of spontaneous breast cancer metastasis to lung [3].
References:
1.Tanjoni I, Walsh C, Uryu S, et al. PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments. Cancer biology & therapy, 2010, 9(10): 764-777.
2.Tancioni I, Uryu S, Sulzmaier F J, et al. FAK inhibition disrupts a beta5 integrin signaling axis controlling anchorage-independent ovarian carcinoma growth. Molecular Cancer Therapeutics, 2014: molcanther. 1063.2014.
3.Walsh C, Tanjoni I, Uryu S, et al. Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. Cancer biology & therapy, 2010, 9(10): 778.
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PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments.[Pubmed:20234191]
Cancer Biol Ther. 2010 May 15;9(10):764-77.
Tumor cells can grow in an anchorage-independent manner. This is mediated in part through survival signals that bypass normal growth restraints controlled by integrin cell surface receptors. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase that associates with integrins and modulates various cellular processes including growth, survival, and migration. As increased FAK expression and tyrosine phosphorylation are associated with tumor progression, inhibitors of FAK are being tested for anti-tumor effects. Here, we analyze PND-1186, a substituted pyridine reversible inhibitor of FAK activity with a 50% inhibitory concentration (IC50) of 1.5 nM in vitro. PND-1186 has an IC50 of ~100 nM in breast carcinoma cells as determined by anti-phospho-specific immunoblotting to FAK Tyr-397. PND-1186 did not alter cSrc or p130Cas tyrosine phosphorylation in adherent cells, yet functioned to restrain cell movement. Notably, 1.0 microM PND-1186 (>5-fold above IC50) had limited effects on cell proliferation. However, under non-adherent conditions as spheroids and as colonies in soft agar, 0.1 microM PND-1186 blocked FAK and p130Cas tyrosine phosphorylation, promoted caspase-3 activation, and triggered cell apoptosis. PND-1186 inhibited 4T1 breast carcinoma subcutaneous tumor growth correlated with elevated tumor cell apoptosis and caspase 3 activation. Addition of PND-1186 to the drinking water of mice was well tolerated and inhibited ascites- and peritoneal membrane-associated ovarian carcinoma tumor growth associated with the inhibition of FAK Tyr-397 phosphorylation. Our results with low-level PND-1186 treatment support the conclusion that FAK activity selectively promotes tumor cell survival in three-dimensional environments.
Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models.[Pubmed:20234193]
Cancer Biol Ther. 2010 May 15;9(10):778-90.
Tumor metastasis is a leading cause of cancer-related death. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase recruited to integrin-mediated matrix attachment sites where FAK activity is implicated in the control of cell survival, migration, and invasion. Although genetic studies support the importance of FAK activity in promoting tumor progression, it remains unclear whether pharmacological FAK inhibition prevents tumor metastasis. Here, we show that the FAK inhibitor PND-1186 blocks FAK Tyr-397 phosphorylation in vivo and exhibits anti-tumor efficacy in orthotopic breast carcinoma mouse tumor models. PND-1186 (100 mg/kg intraperitoneal, i.p.) showed promising pharmacokinetics (PK) and inhibited tumor FAK Tyr-397 phosphorylation for 12 hours. Oral administration of 150 mg/kg PND-1186 gave a more sustained PK profile verses i.p., and when given twice daily, PND-1186 significantly inhibited sygeneic murine 4T1 orthotopic breast carcinoma tumor growth and spontaneous metastasis to lungs. Moreover, low-level 0.5 mg/ml PND-1186 ad libitum administration in drinking water prevented oncogenic KRAS- and BRAF-stimulated MDA-MB-231 breast carcinoma tumor growth and metastasis with inhibition of tumoral FAK and p130Cas phosphorylation. Although PND-1186 was not cytotoxic to cells in adherent culture, tumors from animals receiving PND-1186 exhibited increased TUNEL staining, decreased leukocyte infiltrate and reduced tumor-associated splenomegaly. In vitro, PND-1186 reduced tumor necrosis factor-a triggered interleukin-6 cytokine expression, indicating that FAK inhibition may impact tumor progression via effects on both tumor and stromal cells. As oral administration of PND-1186 also decreased experimental tumor metastasis, PND-1186 may therefore be useful clinically to curb breast tumor progression.
