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Purity: ≥98%
Defactinib HCl (formerly known as VS-6063 HCl, PF-04554878 HCl) is a novel, potent, selective, and orally bioactive small molecule inhibitor of the FAK (focal adhesion kinase), it inhibits the phosphorylation of FAK at the Tyr397 site in a time- and dose-dependent manner. FAK is an essential component of numerous oncogenic pathways and is a nonreceptor tyrosine kinase. It has been documented that several tumor types, such as ovarian, colon, and breast cancers, have elevated FAK expression. Defactinib may therefore have antitumor effects because it inhibits FAK. Tumor cell migration, proliferation, and survival may be inhibited by defactinib's inhibition of FAK, which also inhibits integrin-mediated activation of multiple downstream signal transduction pathways, such as ERK, JNK/MAPK, and PI3K/Akt.
| Targets |
FAK
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| ln Vitro |
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| ln Vivo |
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| Enzyme Assay |
In a manner that was dependent on both time and dosage, defactinib prevented FAK phosphorylation at the Tyr397 site. Defactinib and paclitaxel together significantly reduced proliferation and enhanced apoptosis, leading to tumor weight reductions of 92.7% to 97.9%. Data from RPPA indicated that in taxane-resistant cell lines, defactinib lowered AKT and YB-1 levels. In taxane-resistant cells, FAK inhibition improved chemosensitivity through a mechanism that was dependent on AKT and reduced YB-1 phosphorylation and, consequently, CD44. Increased nuclear YB-1 expression (χ²) = 37.7; P <.001) was correlated with nuclear FAK expression in human ovarian cancer samples. A statistically significant worse median overall survival (24.9 vs 67.3 months; hazard ratio = 2.64; 95% confidence interval = 1.38 to 5.05; P =.006) was linked to the coexpression of nuclear FAK and YB-1.
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| Cell Assay |
The MTT assay is performed after 96 hours of treatment with increasing concentrations of defactinib for ovarian cancer cells. Experiments carried out in triplicate validate the results.
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| Animal Protocol |
Mice: The antitumor effects of defactinib are assessed by intraperitoneal injection of SKOV3ip1, SKOV3-TR, HeyA8, and HeyA8-MDR cells. Mice are randomized into four groups of ten (control, PTX alone, Defactinib alone, and PTX plus Defactinib) one week after the tumor cell injection. Three to four weeks later, treatment is started. Weekly intraperitoneal injections of PTX (2 mg/kg for SKOV3ip1 and SKOV3-TR) or 2.5 mg/kg for HeyA8 and HeyA8-MDR) are administered; twice-daily oral administration of defactinib (25 mg/kg) is recommended. HBSS was administered intraperitoneally once a week to control mice, while vehicle was given twice daily. Day 35 (SKOV3ip1 or SKOV3-TR), Day 28 (HeyA8 or HeyA8-MDR), or when any mouse appears moribund are the dates at which the mice are killed after being observed every day for side effects of the therapy. The total weight of the body, the mass and incidence of the tumor, and the quantity of tumor nodules are noted. The three methods used to treat tumors are formalin fixation, paraffin embedding, and snap freezing in a liquid nitrogen-based optimal cutting temperature (OCT) compound.
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| References |
| Molecular Formula |
C20H22CLF3N8O3S
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|---|---|
| Molecular Weight |
546.95
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| Exact Mass |
546.1176199
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| Elemental Analysis |
C, 43.92; H, 4.05; Cl, 6.48; F, 10.42; N, 20.49; O, 8.78; S, 5.86
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| CAS # |
1073160-26-5
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| Related CAS # |
Defactinib;1073154-85-4
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| Appearance |
Solid powder
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| SMILES |
CNC(=O)C1=CC=C(C=C1)NC2=NC=C(C(=N2)NCC3=NC=CN=C3N(C)S(=O)(=O)C)C(F)(F)F.Cl
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| InChi Key |
RCHQNUQAHJNRBY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H21F3N8O3S.ClH/c1-24-18(32)12-4-6-13(7-5-12)29-19-28-10-14(20(21,22)23)16(30-19)27-11-15-17(26-9-8-25-15)31(2)35(3,33)34;/h4-10H,11H2,1-3H3,(H,24,32)(H2,27,28,29,30);1H
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| Chemical Name |
N-methyl-4-[[4-[[3-[methyl(methylsulfonyl)amino]pyrazin-2-yl]methylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide;hydrochloride
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| Synonyms |
VS-6063 HCl; PF-04554878 HCl; Defactinib hydrochloride; Defactinib HCl; VS6063 HCl; VS 6063 HCl; VS-6063 HCl; PF04554878 HCl; PF 04554878 HCl; PF4554878 HCl; PF-4554878 HCl; PF4554878 HCl
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.67 mg/mL (1.22 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.67 mg/mL (1.22 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 0.67 mg/mL (1.22 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 5% DMSO+50% PEG 300+5% Tween 80+ddH2O: 5mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8283 mL | 9.1416 mL | 18.2832 mL | |
| 5 mM | 0.3657 mL | 1.8283 mL | 3.6566 mL | |
| 10 mM | 0.1828 mL | 0.9142 mL | 1.8283 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04439331 | Active Recruiting |
Drug: Defactinib Hydrochloride | Refractory Lymphoma Advanced Lymphoma |
National Cancer Institute (NCI) |
August 12, 2015 | Phase 2 |
| NCT04720417 | Active Recruiting |
Drug: Defactinib Hydrochloride Procedure: Biopsy |
Metastatic Uveal Melanoma | Thomas Jefferson University | January 26, 2021 | Phase 2 |
| NCT02465060 | Active Recruiting |
Drug: Defactinib Drug: Defactinib Hydrochloride |
Lymphoma Melanoma |
National Cancer Institute (NCI) |
August 17, 2015 | Phase 2 |
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 In vitro biological effects of VS-6063 on taxane-sensitive and taxane-resistant cell lines.J Natl Cancer Inst.2013 Oct 2;105(19):1485-95. |
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 In vivo effects of VS-6063 combined with paclitaxel (PTX).J Natl Cancer Inst.2013 Oct 2;105(19):1485-95. |
 VS-6063 restores YB-1–mediated paclitaxel (PTX) resistance.J Natl Cancer Inst.2013 Oct 2;105(19):1485-95. |
 VS-6063 downregulated YB-1 phosphorylation and nuclear translocation in taxane-resistant cells by an AKT-dependent pathway.J Natl Cancer Inst.2013 Oct 2;105(19):1485-95. |
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 FAK inhibition or silencing of YB-1 downregulates the expression of CD44.J Natl Cancer Inst.2013 Oct 2;105(19):1485-95. |
Impact of pFAK (Tyr 397) and pYB-1 (Ser 102) expressions on patient survival.J Natl Cancer Inst.2013 Oct 2;105(19):1485-95. |
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