Defactinib

Defactinib
	Skeletal formula and ball-and-stick model of defactinib
Clinical data
Other names	PF-04554878, VS-6063
Legal status
Legal status	Investigational New Drug;
Identifiers
	IUPAC name N-methyl-4-[[4-[[3-[methyl(methylsulfonyl)amino]pyrazin-2-yl]methylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide;
CAS Number	1073154-85-4;
PubChem CID	25117126;
DrugBank	DB12282;
ChemSpider	32695161;
UNII	53O87HA2QU;
KEGG	D10618;
ChEMBL	ChEMBL3137331;
PDB ligand	7KD (PDBe, RCSB PDB);
CompTox Dashboard (EPA)	DTXSID901025937 ;
Chemical and physical data
Formula	C20H21F3N8O3S
Molar mass	510.50 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CNC(=O)C1=CC=C(C=C1)NC2=NC=C(C(=N2)NCC3=NC=CN=C3N(C)S(=O)(=O)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); Key:FWLMVFUGMHIOAA-UHFFFAOYSA-N;

Defactinib (INN, codenamed VS-6063) is an inhibitor of PTK2, also known as focal adhesion kinase (FAK), Pyk2, and MELK which was developed by Pfizer and licensed to Verastem Oncology as a potential treatment for solid tumors.

Development for mesothelioma was discontinued in 2015 due to lack of efficacy in a placebo-controlled phase II trial.^[1]^[2] Subsequent research in patients with specific NF2 mutations also found limited activity.^[3]

As of 2022, it remains in trials in combination with other medications for other types of cancer.

As of 2025 it has been approved by FDA in combination with avutometinib for adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy.

References

^ Nathan VL (2015-09-28). "Verastem stops cancer therapy development; shares plunge" (Press release). Reuters. Retrieved 2022-06-05.
^ Fennell DA, Baas P, Taylor P, Nowak AK, Gilligan D, Nakano T, et al. (April 2019). "Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma: COMMAND-A Double-Blind, Randomized, Phase II Study". Journal of Clinical Oncology. 37 (10): 790–798. doi:10.1200/JCO.2018.79.0543. PMID 30785827. S2CID 73478275.
^ Jackman DM, Jegede O, Zauderer MG, Mitchell EP, Zwiebel J, Gray RJ, et al. (2021-05-20). "A phase 2 study of defactinib (VS-6063) in patients with NF2 altered tumors: Results from NCI-match (EAY131) subprotocol U.". Journal of Clinical Oncology. 39 (15_suppl). American Society of Clinical Oncology (ASCO): 3087. doi:10.1200/jco.2021.39.15_suppl.3087. ISSN 0732-183X. S2CID 236401789.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-combination-avutometinib-and-defactinib-kras-mutated-recurrent-low

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[1] Nathan VL (2015-09-28). "Verastem stops cancer therapy development; shares plunge" (Press release). Reuters. Retrieved 2022-06-05.

[2] Fennell DA, Baas P, Taylor P, Nowak AK, Gilligan D, Nakano T, et al. (April 2019). "Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma: COMMAND-A Double-Blind, Randomized, Phase II Study". Journal of Clinical Oncology. 37 (10): 790–798. doi:10.1200/JCO.2018.79.0543. PMID 30785827. S2CID 73478275.

[Jackman_Jegede_Zauderer_Mitchell_pp._3087–3087-3] Jackman DM, Jegede O, Zauderer MG, Mitchell EP, Zwiebel J, Gray RJ, et al. (2021-05-20). "A phase 2 study of defactinib (VS-6063) in patients with NF2 altered tumors: Results from NCI-match (EAY131) subprotocol U.". Journal of Clinical Oncology. 39 (15_suppl). American Society of Clinical Oncology (ASCO): 3087. doi:10.1200/jco.2021.39.15_suppl.3087. ISSN 0732-183X. S2CID 236401789.

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