1073154-85-4

Basic information

• Product Name: Defactinib
• Synonyms: Defactinib;VS 6063;VS6063;VS-6063;Defactinib(PF-04554878);N-methyl-4-(4-((3-(N-methylmethan-3-ylsulfonamido)pyrazin-2-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzamide;N-methyl-4-((4-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide Defactinib(PF-04554878)(VS-6063);N-Methyl-4-[[4-[[[3-[methyl(methylsulfonyl)amino]-2-pyrazinyl]methyl]amino]-5-(trifluoromethyl)-2-pyrimidinyl]amino]benzamide
• CAS NO: 1073154-85-4
• Molecular Formula: C₂₀H₂₁F₃N₈O₃S
• Molecular Weight: 510.4927496
• Product Categories: Inhibitors
• Mol File: 1073154-85-4.mol
• Article Data: 2

Chemical Properties

• Appearance: /
• Density: 1.495±0.06 g/cm3(Predicted)
• Storage Temp.: -20°C (des.)
• Solubility: Soluble in DMSO (up to at least 25mg/ml)
• PKA: 15.16±0.46(Predicted)
• Stability: Stable for 1 year as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: Defactinib(CAS DataBase Reference)
• NIST Chemistry Reference: Defactinib(1073154-85-4)
• EPA Substance Registry System: Defactinib(1073154-85-4)

Safety Data

• Hazardous Substances Data: 1073154-85-4(Hazardous Substances Data)

Usage

Description

Defactinib, also known as VS-6063, is a selective and orally active focal adhesion kinase (FAK) inhibitor that plays a crucial role in various oncogenic pathways. It is a small molecule compound that has demonstrated potential in the treatment of cancer by targeting the FAK pathway, which is involved in cell proliferation, survival, and migration.

Uses

Used in Cancer Treatment:
Defactinib is used as an anticancer agent for treating cancer patients. It works by inhibiting the FAK pathway, which is often dysregulated in various types of cancer. By inhibiting FAK, Defactinib decreases cell proliferation and increases apoptosis, leading to a reduction in tumor growth.
Used in Overcoming Drug Resistance:
Defactinib is used as a chemosensitizer for restoring the chemosensitivity of taxane-resistant cancer cells to paclitaxel. It achieves this by inhibiting FAK autophosphorylation, which is a key event in the development of drug resistance. This restoration of chemosensitivity allows for more effective treatment of cancer patients who have developed resistance to conventional chemotherapy.
Used in Ovarian Cancer Treatment:
Defactinib is used as a therapeutic agent for ovarian cancer. It has been shown to inhibit FAK and augment the action of paclitaxel, a commonly used chemotherapy drug, in suppressing the growth and number of ovarian cancer cell tumors in mice. This suggests that Defactinib could be a valuable addition to the treatment regimen for ovarian cancer patients.

References

1) Jones?et al.?(2015),?A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors;?Invest. New Drugs?33?1100 2) Kolev?et al.?(2017),?Inhibition of FAK kinase activity preferentially targets cancer stem cells;?Oncotarget?8?51733 3) Marcucci?et al.?(2016),?Anti-Cancer Stem-like Cell Compounds in Clinical Development – An Overview and Critical Appraisal;?Front. Oncol.?6?115 4) Ring?et al.?(2015),?FAK/PYK2 inhibitors defactinib and VS-4718 enhance immune checkpoint inhibitor efficacy;?J. Immunother. Cancer?3?354 5) NCT02546531 6) Jiang?et al.?(2016),?Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy;?Nat. Med.?22?851

Upstream product

• 6274-22-2 4-amino-N-methyl-benzamide 
• 1073160-19-6 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzamide 

Relevant articles and documents

Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2

There is increasing evidence of a significant correlation between prolonged drug-target residence time and increased drug efficacy. Here, we report a structural rationale for kinetic selectivity between two closely related kinases: focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). We found that slowly dissociating FAK inhibitors induce helical structure at the DFG motif of FAK but not PYK2. Binding kinetic data, high-resolution structures and mutagenesis data support the role of hydrophobic interactions of inhibitors with the DFG-helical region, providing a structural rationale for slow dissociation rates from FAK and kinetic selectivity over PYK2. Our experimental data correlate well with computed relative residence times from molecular simulations, supporting a feasible strategy for rationally optimizing ligand residence times. We suggest that the interplay between the protein structural mobility and ligand-induced effects is a key regulator of the kinetic selectivity of inhibitors of FAK versus PYK2.