PF-04880594

PF-04880594 is a potent and selective RAF inhibitor. PF-04880594 inhibits both wild-type and mutant BRAF and CRAF. PF-04880594 shows antitumor activity[1].

Research Areas >> Cancer

Signaling Pathways >> MAPK/ERK Pathway >> Raf

Braf

CRAF

PF-04880594 (100 nM, 48 h) causes ERK activation and stimulation of IL-8 release, both of which are blocked by PD-0325901 (HY-10254) treatment[1]. Western Blot Analysis[1] Cell Line: HL-60 Concentration: 100 nM alone or in combination with 100 nM PD-0325901 Incubation Time: 48 h Result: Induced ERK phosphorylation and induced IL-8 production. PD-0325901 treatment blocked the induction.

PF-04880594 (10 mg/kg) induces ERK phosphorylation and BRAF-CRAF dimerization in multiple epithelial tissues in mice and the induction can be attenuated by PD0325901[1]. PF-04880594 (0-40 mg/kg, twice daily for 3 weeks) induces epithelial hyperplasia in mice and the induction is prevented by PD0325901[1]. Animal Model: Nude mice[1] Dosage: 10 mg/kg alone or in combination with 0.5 mg/kg PD-0325901 Administration: An am and pm dose on day 1 and then an am dose on day 2 approximately 2 hours before the animals were necropsied and the tissues harvested Result: Induced ERK phosphorylation in urinary bladder, tongue, skin, and esophagus tissues.The induction of ERK phosphorylation was attenuated by cotreatment with 0.5 mg/kg PD0325901. Animal Model: Nude mice (6–8 weeks old)[1] Dosage: 10, 20 and 40 mg/kg alone or in combination with 0.1, 0.3, 0.5, 1.0, or 2.5 mg/kg PD-0325901 Administration: Twice daily for 3 weeks Result: Tissues treated with the RAF inhibitor alone display the microscopic pathology typical of unopposed BRAF inhibition. Hyperplasia in nonglandular stomach epithelium was blocked by PD-0325901.

[1]. Torti VR, et al. Epithelial tissue hyperplasia induced by the RAF inhibitor PF-04880594 is attenuated by a clinically well-tolerated dose of the MEK inhibitor PD-0325901. Mol Cancer Ther. 2012 Oct;11(10):2274-83.