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defactinib   Click here for help

GtoPdb Ligand ID: 7910

Synonyms: Avmapki Fakzynja (avutometinib + defactinib co-pack) | PF-04554878 | VS-6063
Approved drug PDB Ligand
defactinib is an approved drug
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].
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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/)
No information available.
Summary of Clinical Use Click here for help
Defactinib (PF-04554878/VS-6063) was progressed to clinical evaluations in a variety of advanced solid malignancies [3,11]. The EMA issued orphan drug designations for the treatment of malignant mesothelioma and ovarian cancers in 2013 and 2015 respectively. The FDA granted accelerated approval for the combination of avutometinib and defactinib in May 2025, indicated to treat KRAS-mutated recurrent low-grade serous ovarian cancer (following previous systemic therapy)
Mechanism Of Action and Pharmacodynamic Effects Click here for help
The tyrosine kinase FAK is a key signal transducer for integrins and growth factors, that is upregulated in many tumor cell types and is involved in tumor cell invasion, migration and proliferation [7]. Autophosphorylation of FAK at Tyr397 mediates interation with downstream signalling molecules including ERK, JNK/MAPK and PI3K/Akt [8,10]. FAK inhibition is therefore likely to prevent the activation of these signal transduction pathways, thus inhibiting tumor cell migration, proliferation and survival [1]. In addition, FAK inhibition with defactinib has been reported to overcome YB-1 (YBX1; P67809)-mediated paclitaxel resistance in in vitro tumour cell models, via an Akt-dependent pathway [4].
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT06369259 Open-label Phase 2 Study of Avutometinib (RAF/MEK Clamp) in Combination With Defactinib (FAK Inhibitor) and Cetuximab in Patients With Unresectable, Anti-EGFR-Refractory Advanced Colorectal Cancer Phase 2 Interventional M.D. Anderson Cancer Center
NCT06394804 A Study of Avutometinib, Defactinib, and Letrozole in People With Low-Grade Serous Ovarian Cancer Phase 2 Interventional Memorial Sloan Kettering Cancer Center
NCT02465060 Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial) Phase 2 Interventional National Cancer Institute (NCI) 12
NCT06072781 A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer Phase 3 Interventional Verastem, Inc. 2