Defactinib

Defactinib
	Skeletal formula and ball-and-stick model of defactinib
Clinical data
Other names	PF-04554878, VS-6063
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]

The co-packaged medication avutometinib/defactinib was approved for medical use in the United States in May 2025.^[4]^[5]

References

^ Nathan VL (28 September 2015). "Verastem stops cancer therapy development; shares plunge" (Press release). Reuters. Retrieved 5 June 2022.
^ 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. (20 May 2021). "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.
^ "FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer". U.S. Food and Drug Administration. 8 May 2025. Archived from the original on 8 May 2025. Retrieved 16 May 2025. This article incorporates text from this source, which is in the public domain.
^ "FDA Approves the Avmapki Fakzynja Combination Therapy as the First-Ever Treatment for Adult Patients with KRAS-mutated Recurrent Low-Grade Serous Ovarian Cancer". Verastem (Press release). Retrieved 16 May 2025.

[1] Nathan VL (28 September 2015). "Verastem stops cancer therapy development; shares plunge" (Press release). Reuters. Retrieved 5 June 2022.

[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. (20 May 2021). "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.

[FDA_Avmapki_Fakzynja-4] "FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer". U.S. Food and Drug Administration. 8 May 2025. Archived from the original on 8 May 2025. Retrieved 16 May 2025. This article incorporates text from this source, which is in the public domain.

[Verastem_PR-5] "FDA Approves the Avmapki Fakzynja Combination Therapy as the First-Ever Treatment for Adult Patients with KRAS-mutated Recurrent Low-Grade Serous Ovarian Cancer". Verastem (Press release). Retrieved 16 May 2025.

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