Defactinib

Defactinib (VS-6063, PF-04554878) is a potent, selective and orally active FAK inhibitor, selectively inhibits pFAK (Tyr397) in a dose-dependent manner in cancer cell lines; shows no statistically significant changes in FAK phosphorylation at the other residues (Tyr 576/577, Tyr 925, or Tyr 861), also inhibits Pyk2 Tyr402 phosphorylation in HeyA8 cells; markedly decreases proliferation and increases apoptosis combined with paclitaxel, reduces levels of AKT and YB-1 in taxane-resistant cell lines; significantly reduces tumor growth, synergized with the mTOR inhibitor everolimus in xenograft models of pancreatic tumor.Lung Cancer Phase 2 Clinical (In Vitro) :Defactinib (VS-6063) inhibits FAK phosphorylation at the Tyr397 site in a time- and dose-dependent manner. RPPA data shows that Defactinib reduces levels of AKT and YB-1 in taxane-resistant cell lines. The expression of pFAK (Tyr397) is statistically significantly inhibited by Defactinib in a dose-dependent manner in all cell lines. Defactinib inhibits pFAK (Tyr397) expression within 3 hours, with a gradual return of expression by 48 hours. (In Vivo) :Defactinib (VS-6063) doses of 25 mg/kg twice a day or greater statistically significantly inhibits pFAK (Tyr397) at 3 hours, with return of expression noted by 24 hours. Therefore, administration of Defactinib at 25 mg/kg twice a day is selected as the dosing schedule for subsequent therapy experiments. For therapy experiments, female nude mice bearing HeyA8 tumors in the peritoneal cavity are randomly divided into 4 groups (n=10 per group) : 1) vehicle orally twice daily and phosphate-buffered saline intraperitoneally weekly (control) ; 2) Defactinib 25 mg/kg orally twice daily; 3) PTX intraperitoneally weekly; and 4) both VDefactinib 25 mg/kg orally twice daily and PTX intraperitoneally weekly. There is an 87.4% reduction in tumor weight by PTX monotherapy in the HeyA8 model, and combination therapy resulted in the greatest tumor weight reduction, with a 97.9% reduction (P=0.05 compared with PTX) . In the SKOV3ip1 model, a 92.7% tumor weight reduction is observed in the combination group compared with PTX (P<0.001) .

1073154-85-4

VS-6063 | VS6063 | PF04554878 | PF-04554878

>98% (HPLC)

DMSO: ≥ 39 mg/mL

CNC (=O) C1=CC=C (NC2=NC=C (C (NCC3=NC=CN=C3N (C) S (C) (=O) =O) =N2) C (F) (F) F) C=C1

C20H21F3N8O3S

510.4927

Storage temperature: -20°C. Stability: ≥ 2 years

For research use only.