LY2874455

LY2874455 is a potent, selective pan-FGFR inhibitor with IC50 of 2.8/2.6/6.4/6 nM for FGFR1/2/3/4, respectively; inhibits FGFR2 phosphorylation in SNU-16 and KATO-III cells with IC50 of 0.8 and1.5 nM, also inhibits the phosphorylation of FRS2, an immediate downstream target of FGFR, with a similar potency of 0.8 to 1.5 nM; exhibits a potent activity against FGF/FGFR-mediated signaling in several cancer cell lines and shows an excellent broad spectrum of antitumor activity in several tumor xenograft models representing the major FGF/FGFR relevant tumor histologies including lung, gastric, and bladder cancers and multiple myeloma.Blood Cancer Phase 1 Clinical (In Vitro) :LY2874455 potently inhibits the Erk phosphorylation induced by FGF2 and FGF9 in both cell lines in a dose-dependent manner, with average IC50 values of 0.3 to 0.8 nM. LY2874455 indeed inhibits FGFR2 phosphorylation in SNU-16 and KATO-III cells, with estimated IC50 values of 0.8 and 1.5 nM, respectively. In addition, LY2874455 inhibits the phosphorylation of FRS2, an immediate downstream target of FGFR in these cell lines, again with a similar potency of 0.8 to 1.5 nM. Together, these results suggest that LY2874455 inhibits FGFR in the cell. The relative IC50 values of LY2874455 for KMS-11, OPM-2, L-363, and U266 cells are determined to be 0.57, 1.0, 60.4, and 290.7 nM, respectively. (In Vivo) :LY2874455 exhibits a rapid, robust, dose-dependent inhibition of tumor growth in all 4 models tested. Importantly, this molecule causes a significant regression of tumor growth in the RT-112, SNU-16, and OPM-2 tumor models, especially when dosed at 3 mg/kg twice a day. Also, LY2874455 exhibits an excellent pharmacokinetic/pharmacodynamic relationship as shown by its dose-dependent inhibition of the tumor growth at TED50 and TED90 (1 and 3 mg/kg, respectively) . When tested in the RT-112 tumor xenograft model on an intermittent dosing schedule (twice a day 1 week on and 1 week off or twice a day 2 days on and 2 days off), LY2874455 is also efficacious. When rats are dosed with LY2874455 at 1 and 3 mg/kg, which is 2.6- and 7.7-fold over the TED50 (0.39 mg/kg) obtained in the rat heart IVTI assay, respectively, there are no significant changes observed in blood pressure. However, when rats are dosed with LY2874455 at 10 mg/kg, which is 25.6-fold over the TED50, there are significant increases observed in arterial pressures.