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

PF-04880594 (100 nM, 48 h) causes ERK activation and stimulation of IL-8 release, both blocked by the treatment of PD-0325901 [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, administered at 10 mg/kg, was observed to induce ERK phosphorylation and BRAF-CRAF dimerization across multiple epithelial tissues in mice, with the effects being mitigable by co-treatment with PD0325901. Additionally, when administered at doses ranging from 0-40 mg/kg twice daily over three weeks, PF-04880594 led to epithelial hyperplasia in mice, a condition that was effectively prevented by PD0325901. In experiments involving nude mice, a single day’s administration of 10 mg/kg PF-04880594, followed by a dose 2 hours before necropsy on the next day, resulted in ERK phosphorylation within urinary bladder, tongue, skin, and esophagus tissues, which was attenuated by a concurrent administration of 0.5 mg/kg PD0325901. Continuous administration of PF-04880594, at dosages of 10, 20, and 40 mg/kg in combination with varying doses of PD-0325901 (0.1, 0.3, 0.5, 1.0, or 2.5 mg/kg) for three weeks, highlighted microscopic pathologies typical of unopposed BRAF inhibition and reported that hyperplasia in nonglandular stomach epithelium could be obstructed by PD0325901.