defactinib   Click here for help

GtoPdb Ligand ID: 7910

Synonyms: PF-04554878 | VS-6063
PDB Ligand
Compound class: Synthetic organic
Comment: Defactinib (VS-6063) is an orally bioavailable, second generation, small-molecule focal adhesion kinase (FAK) inhibitor with potential antiangiogenic and antineoplastic activities [1,9]. Phase 1 clinical trial results show that Defactinib is well tolerated and exhibits some clinical efficacy in patients (albeit in only two reported subjects) with advanced solid tumours [3,11].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species

defactinib is commercially available from our sponsors

2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 11
Hydrogen bond donors 3
Rotatable bonds 10
Topological polar surface area 150.48
Molecular weight 510.14
XLogP 2.2
No. Lipinski's rules broken 1

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES CNC(=O)c1ccc(cc1)Nc1ncc(c(n1)NCc1nccnc1N(S(=O)(=O)C)C)C(F)(F)F
Isomeric SMILES CNC(=O)c1ccc(cc1)Nc1ncc(c(n1)NCc1nccnc1N(S(=O)(=O)C)C)C(F)(F)F
InChI 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)
InChI Key FWLMVFUGMHIOAA-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. A-González N, Castrillo A. (2011)
Liver X receptors as regulators of macrophage inflammatory and metabolic pathways.
Biochim Biophys Acta, 1812 (8): 982-94. [PMID:21193033]
2. Golubovskaya VM, Cance WG. (2007)
Focal adhesion kinase and p53 signaling in cancer cells.
Int Rev Cytol, 263: 103-53. [PMID:17725966]
3. Jones SF, Siu LL, Bendell JC, Cleary JM, Razak AR, Infante JR, Pandya SS, Bedard PL, Pierce KJ, Houk B 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 (5): 1100-7. [PMID:26334219]
4. Kang Y, Hu W, Ivan C, Dalton HJ, Miyake T, Pecot CV, Zand B, Liu T, Huang J, Jennings NB et al.. (2013)
Role of focal adhesion kinase in regulating YB-1-mediated paclitaxel resistance in ovarian cancer.
J Natl Cancer Inst, 105 (19): 1485-95. [PMID:24062525]
5. Klaeger S, Heinzlmeir S, Wilhelm M, Polzer H, Vick B, Koenig PA, Reinecke M, Ruprecht B, Petzoldt S, Meng C et al.. (2017)
The target landscape of clinical kinase drugs.
Science, 358 (6367). [PMID:29191878]
6. Lin HM, Lee BY, Castillo L, Spielman C, Grogan J, Yeung NK, Kench JG, Stricker PD, Haynes AM, Centenera MM et al.. (2018)
Effect of FAK inhibitor VS-6063 (defactinib) on docetaxel efficacy in prostate cancer.
Prostate, 78 (4): 308-317. [PMID:29314097]
7. Owens LV, Xu L, Dent GA, Yang X, Sturge GC, Craven RJ, Cance WG. (1996)
Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer.
Ann Surg Oncol, 3 (1): 100-5. [PMID:8770310]
8. Polte TR, Hanks SK. (1995)
Interaction between focal adhesion kinase and Crk-associated tyrosine kinase substrate p130Cas.
Proc Natl Acad Sci USA, 92 (23): 10678-82. [PMID:7479864]
9. Provenzano PP, Keely PJ. (2009)
The role of focal adhesion kinase in tumor initiation and progression.
Cell Adh Migr, 3 (4): 347-50. [PMID:19690467]
10. Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT. (1994)
Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src.
Mol Cell Biol, 14 (3): 1680-8. [PMID:7509446]
11. Shimizu T, Fukuoka K, Takeda M, Iwasa T, Yoshida T, Horobin J, Keegan M, Vaickus L, Chavan A, Padval M et al.. (2016)
A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors.
Cancer Chemother Pharmacol, 77 (5): 997-1003. [PMID:27025608]