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Defactinib (formerly known as VS-6063, PF-04554878) is a selective, ATP-competitive and orally bioactive small molecule inhibitor of the FAK (focal adhesion kinase) with potential antitumor activity. It inhibits the phosphorylation of FAK at the Tyr397 site in a time- and dose-dependent manner. FAK is a nonreceptor tyrosine kinase that plays a vital role in many oncogenic pathways. Increased FAK expression has been reported in a number of tumor types, including breast, colon, and ovarian cancers. Therefore, as an inhibitor of FAK, defactinib has potential antineoplastic activities.
Physicochemical Properties
| Molecular Formula | C20H21F3N8O3S |
| Molecular Weight | 510.49 |
| Exact Mass | 510.14 |
| CAS # | 1073154-85-4 |
| Related CAS # | Defactinib hydrochloride;1073160-26-5 |
| PubChem CID | 25117126 |
| Appearance | White to off-white solid powder |
| Density | 1.5±0.1 g/cm3 |
| Index of Refraction | 1.616 |
| LogP | -0.74 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 13 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 35 |
| Complexity | 804 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | FWLMVFUGMHIOAA-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C20H21F3N8O3S/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) |
| Chemical Name | N-methyl-4-((4-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide |
| Synonyms | VS-6063; PF-04554878; VS6063; VS 6063; PF04554878; PF 04554878; PF4554878; |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| ln Vitro | FAK phosphorylation at Tyr397 is inhibited by defactinib (VS-6063) in a dose- and time-dependent manner. Defactinib lowers AKT and YB-1 levels in taxane-resistant cell lines, according to RPPA findings. Defactinib dose-dependently and statistically significantly suppressed the expression of pFAK (Tyr397) in all cell lines. Within three hours, defactinib blocks the expression of pFAK (Tyr397), and within 48 hours, expression progressively returns [1]. | ||
| ln Vivo | Within three hours, defactinib (VS-6063) at doses of 25 mg/kg twice day or more induced statistically significant suppression of pFAK (Tyr397), and within twenty-four hours, expression was restored. As a result, the dosage schedule for the ensuing treatment trials was determined to be Defactinib at 25 mg/kg twice day. In the course of the treatment trials, four groups of ten female nude mice with intraperitoneal HeyA8 tumors were randomly assigned: 1) oral administration of vehicle twice a day and weekly intraperitoneal injection of phosphate buffered saline (control); 2) Defactinib 25 mg/kg PO twice a day; 3) PTX weekly IP; and 4) VDefactinib 25 mg/kg PO twice a day. The HeyA8 model showed that PTX monotherapy reduced tumor weight by 87.4%, however combination therapy reduced tumor weight by the highest amount, 97.9% (P=0.05 compared with PTX). Tumor weight decreased in the combination therapy group in the SKOV3ip1 model by 92.7% as compared to PTX (P<0.001)[1]. | ||
| Animal Protocol |
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| References |
[1]. Role of focal adhesion kinase in regulating YB-1-mediated resistance in ovarian cancer. J Natl Cancer Inst. 2013 Oct 2;105(19):1485-95. |
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| Additional Infomation |
Defactinib has been investigated for the treatment of Malignant Pleural Mesothelioma. Defactinib is an orally bioavailable, small-molecule focal adhesion kinase (FAK) inhibitor with potential antiangiogenic and antineoplastic activities. Defactinib inhibits FAK, which may prevent the integrin-mediated activation of several downstream signal transduction pathways, including those involving RAS/MEK/ERK and PI3K/Akt, thus inhibiting tumor cell migration, proliferation, survival, and tumor angiogenesis. The tyrosine kinase FAK, a signal transducer for integrins, is normally activated by binding to integrins in the extracellular matrix (ECM) but may be upregulated and constitutively activated in various tumor cell types. See also: Defactinib Hydrochloride (annotation moved to). |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.90 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.07 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 20.8 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 3: ≥ 2.08 mg/mL (4.07 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 5% DMSO+50% PEG 300+5% Tween 80+ddH2O: 5mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9589 mL | 9.7945 mL | 19.5890 mL | |
| 5 mM | 0.3918 mL | 1.9589 mL | 3.9178 mL | |
| 10 mM | 0.1959 mL | 0.9795 mL | 1.9589 mL |