GSK2256098   Click here for help

GtoPdb Ligand ID: 7939

Synonyms: GSK-2256098
Compound class: Synthetic organic
Comment: GSK2256098 is a small molecule focal adhesion kinase (FAK) inhibitor with potential antiangiogenic and antineoplastic activity [1,3-4].
2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 5
Hydrogen bond donors 3
Rotatable bonds 8
Topological polar surface area 93.1
Molecular weight 414.16
XLogP 4.67
No. Lipinski's rules broken 0
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Canonical SMILES CONC(=O)c1ccccc1Nc1cc(ncc1Cl)Nc1cc(nn1C(C)C)C
Isomeric SMILES CONC(=O)c1ccccc1Nc1cc(ncc1Cl)Nc1cc(nn1C(C)C)C
InChI InChI=1S/C20H23ClN6O2/c1-12(2)27-19(9-13(3)25-27)24-18-10-17(15(21)11-22-18)23-16-8-6-5-7-14(16)20(28)26-29-4/h5-12H,1-4H3,(H,26,28)(H2,22,23,24)
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Summary of Clinical Use Click here for help
Phase 1 clinical trial results are reviewed by Schultze and Fiedler (2011) [4]. Preliminary results indicate some clinical benefit may be achieved in patients with mesothelioma [2], in whom FAK is overactive due to the absence of the neurofibromin 2 (merlin) protein (from the NF2 gene). In such patients GSK2256098 prolongs the period of stable disease (indicative of decreased cell invasion). Further Phase 1 trials are underway (Nov 2014) for various solid tumours, with either GSK2256098 alone (NCT01138033), or in combination with the approved MEK inhibitor, trametinib (NCT01938443; this trial includes mesothelioma patients).
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Cell migration and invasion are key processes in the metastasis of cancer. Focal adhesion kinase (FAK) is crucial to the formation of focal adhesions, and downstream signalling via ERK and PI3K which mediate cell migration, making suppression FAK a potential strategy for novel cancer therapeutics [3]. FAK is normally activated by binding to integrins in the extracellular matrix (ECM) but may be upregulated and constitutively activated in various tumor cell types. GSK2256098 inhibits autophosphorylation of FAK at tyrosine (Y) 397, decreasing its activity, and thereby leading to decreased cell motility (and viability).