PND-1186

Potent FAK inhibitor CAS# 1061353-68-1

PND-1186

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Chemical structure

PND-1186

3D structure

Chemical Properties of PND-1186

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.
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.
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.

Biological Activity of PND-1186

DescriptionPND-1186 is a potent inhibitor of focal adhesion kinase (FAK) with IC50 value of 1.5 nM.
TargetsFAK    
IC501.5 nM     

Protocol

Cell Assay [1]
For cell growth analyses, adherent or suspended cells are treated with PND-1186 for the indicated times, collected as a single cell suspension by limited trypsin treatment, fixed with 70% ethanol, collected by centrifugation and washed with PBS. Cell pellets are resuspended in 300 µL of PBS containing propidium iodide (PI) (10 µg/mL), DNAse-free RNAse (100 µg/mL), and then incubated at 37°C with agitation for 1 h. Samples are analyzed by flow cytometry and cell cycle analyses are performed by ModFit LT3.2 software. Hypodiploid DNA content as a measure of cell apoptosis is detected by PI staining. For cell apoptosis analyses, adherent or suspended cells are treated with PND-1186 and collected as above, stained for phycoerythrin (PE)-conjugated annexin V binding and 7-amino-actinomycin (7-AAD) reactivity, and analyzed within 1 h by flow cytometry. Quadrant gates are positioned based on cell autofluorescence (negative) staurosporine-treated (positive) controls. Apoptosis is calculated to be the percent of annexin V-positive cells. In the soft agar assays, apoptosis is quantified by visual inspection of at least 200 cells and is defined as the appearance of membrane blebbing or cell shrinkage. Apoptosis is also detected by appearance of cleaved caspase-3 antibody reactivity in protein lysates by immunoblotting[1].

Animal Administration [1]
Mice[1] Six to eight week old female C57BL6 and BALB/c mice are used. For subcutaneous tumor growth, 1×106 mCherry-labeled 4T1 cells in 100 µL PBS are injected into the hindflank of Balb/C mice. After 8 days, mice with equal volume tumors (as measured using vernier calipers and determined by length×width2/2) are grouped (n=8 per group) and PND-1186 solubilized in polyethylene glycol 400 (PEG400) in PBS (1:1) is injected (100 µL) subcutaneously in the neck region at 30 mg/kg or 100 mg/kg every 12 hours. Control animals receive PEG400:PBS injections and at 13 days, tumors are imaged in situ using an Olympus OV100 Intravital Fluorescence Molecular Imaging System, tumors are excised and weighed, half is frozen in OCT, and half is solubilized in protein lysis buffer for FAK phosphorylation analyses.

References:
[1]. Tanjoni I, et al. PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments. Cancer Biol Ther. 2010 May 15;9(10):764-77. [2]. Walsh C, et al. Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. Cancer Biol Ther. 2010 May 15;9(10):778-90.

PND-1186 Dilution Calculator

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PND-1186 Molarity Calculator

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Preparing Stock Solutions of PND-1186

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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Background on PND-1186

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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References on PND-1186

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.

Description

PND-1186 (VS-4718; SR-2516) is a potent and reversible inhibitor of FAK with an IC50 of 1.5 nM in cell assay.

Keywords:

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