PF-04217903

PF-04217903 is an orally active, highly selective ATP-competitive c-Met kinase inhibitor with a K_i value of 4.8 nM and a K_d value of 4.5 nM. PF-04217903 blocks c-Met and HGF signaling pathways, inhibits MET phosphorylation, and blocks downstream MAPK, PI3K/AKT and PLCγ1 pathways. PF-04217903 suppresses tumor proliferation, survival, migration, invasion, angiogenesis and metastasis, induces apoptosis, and enhances efferocytosis, Annexin A1 expression and resolution of inflammation. PF-04217903 retains activity against several c-Met mutants (M1131T, V1220I, H1094R). PF-04217903 increases the incidence of subarachnoid hemorrhage and reduces survival rate without altering aneurysm formation, and also prevents lymph node metastasis induced by VEGF inhibition. PF-04217903 is applicable to research related to tumors (pancreas, stomach, lung, brain, colon, breast, kidney, melanoma, etc.), intracranial aneurysms and inflammatory diseases (gouty arthritis, neutrophilic pleuritis)^{[1][2][3][4][5][6][7][8][9]}. In Vitro:PF-04217903 acts as a highly selective c-Met inhibitor, with >1000-fold greater potency for c-Met than for 208 other tested kinases^[1].
PF-04217903 (1 μM) shows biochemical inhibition of IGF1R in kinase selectivity screens, but does not inhibit IGF1R activity in cell-based assays^[8].
PF-04217903 (30 min) potently inhibits wild-type c-Met (K_i = 6.5-7.4 pM) and most oncogenic c-Met mutants, but exhibits drastically reduced potency against c-Met^Y1230C, c-Met^Y1230H, and c-Met^D1228H mutants, and no measurable inhibition of c-Met^D1228H[9].
PF-04217903 (1 h; 20 min) potently inhibits c-Met phosphorylation in cells expressing wild-type or most mutant c-Met (IC₅₀ = 3.1-24 nM), but shows no measurable inhibition (IC₅₀ >10000 nM) in NIH-3T3 cells expressing the c-Met^Y1230C mutant and drastically reduced potency in T47D cells expressing the c-Met^Y1235D mutant^[9].
PF-04217903 (7.8-1000 nM; 1 min association, 5 min dissociation) binds tightly to purified c-Met kinase domain with a K_d of 4.5 nM and a residence time of 180 s^[9].
PF-04217903 (5 μM; 30 min) significantly stabilizes wild-type c-Met and most oncogenic c-Met mutants (T_m shift = 11.6-17.0 °C), but shows minimal stabilization of c-Met^Y1230C (T_m shift = 2.1 °C) and c-Met^Y1230H (T_m shift = 4.4 °C) mutants^[9].
PF-04217903 (6 μg/mL; 1 hour pre-incubation, 3 hours LPS treatment) blocks the HGF-mediated reduction of VCAM-1 and E-selectin expression in human aortic endothelial cells, but has no effect on inflammatory molecule expression in human aortic smooth muscle cells or THP-1 monocytes^[3].
PF-04217903 (10-10000 nM; 6 days) potently inhibits growth of Met-amplified recurrent murine ATC cell lines 34286 (IC₅₀ ~150 nM) and 36934 (IC₅₀ ~50 nM), but shows minimal activity against primary murine ATC and Met-diploid recurrent murine ATC cell lines^[4].
PF-04217903 (10-1000 nM; 1 hour) inhibits Met phosphorylation and downstream Akt/Erk signaling in Met-amplified recurrent murine ATC cell lines, but does not affect these signaling pathways in primary murine ATC or Met-diploid recurrent murine ATC cell lines^[4].
PF-04217903 (153 pM-10 μM; 3 days) inhibits parental GTL16 gastric carcinoma cell viability with an IC₅₀ of 10 nM, but does not inhibit viability in SND1-BRAF fusion-positive resistant GTL16R1 and GTL16R3 clones at concentrations up to 10 μM^[8].
PF-04217903 (2.5 μM; 1 hour) inhibits c-Met^Y1235 phosphorylation in parental GTL16, GTL16R1, and GTL16R3 gastric carcinoma cells, confirming the inhibitor binds and inhibits c-Met catalytic activity in resistant clones^[8].
PF-04217903 (200 nM; 4 hours) inhibits c-Met Y1349 and AKT S473 phosphorylation in parental GTL16, GTL16R1, and GTL16R3 gastric carcinoma cells; it completely blocks ERK phosphorylation in parental GTL16 cells but only partially reduces ERK phosphorylation in resistant clones, with combined treatment with RAFi achieving greater ERK inhibition in resistant clones^[8].
PF-04217903 (≥39 nM/2.5 nM; 3 days) synergizes with RAF inhibitor PF-04880594 or MEK inhibitor PD-0325901 to inhibit viability in SND1-BRAF fusion-positive resistant GTL16R1 and GTL16R3 gastric carcinoma clones, but does not enhance growth inhibition in parental GTL16 cells compared to single-agent treatment^[8].
PF-04217903 (0.5-2.5 μM; 4 months) generates PF-04217903-resistant cell clones from GTL16 gastric carcinoma cells^[8].
PF-04217903 (30 µM; 1-6 h) inhibits LPS/HGF-induced and MSU-induced MET phosphorylation in primary human peripheral blood neutrophils, and induces caspase-dependent apoptosis by increasing cleaved caspase-3 levels and reducing Bcl-xL levels^[5]. In Vivo:PF-04217903 (30 mg/kg; p.o.; daily; 3-6 weeks) reduces the invasiveness and hepatic metastasis of pancreatic neuroendocrine tumors in RIP-Tag2 mice, decreases intratumoral lymphatic vessel density and the invasion of tumor cells into lymphatic vessels, blocks the increased tumor invasiveness induced by VEGF inhibition, extends the median survival to 16.1 weeks as a monotherapy, and extends it to 17.3 weeks when combined with an anti-VEGF antibody^[1][2].
PF-04217903 (30 mg/kg; p.o.; once daily; for 3 consecutive weeks) enhances the anti-tumor growth and anti-invasion effects of Sunitinib in a nude mouse orthotopic Panc-1 pancreatic adenocarcinoma model, and eliminates micrometastases observed with Sunitinib monotherapy^[1].
PF-04217903 (30-45 mg/kg; p.o.; once daily administration) (active compound PF-04217903) exerts potent and selective in vivo growth inhibitory effects on Met-amplified recurrent anaplastic thyroid carcinoma xenografts in nude mice^[4].
PF-04217903 (40 mg/kg; p.o.; once daily; for 25 consecutive days) achieves a 45% tumor growth inhibition (TGI) rate in c-Met-overexpressing SW620 xenograft models, while sustaining inhibition of c-Met phosphorylation and upregulating total c-Met protein expression after treatment^[6].
PF-04217903 (40-50 mg/kg; p.o.; once daily; for 14-31 consecutive days) inhibits tumor growth in c-Met-overexpressing Colo205, MDA-MB-231, and H292 xenograft models^[6].
PF-04217903 (10 mg/kg; p.o.; daily administration; for 21 consecutive days) does not alter intracranial aneurysm formation in a mouse model of intracranial aneurysm, but increases the incidence of subarachnoid hemorrhage to 94% and reduces the survival rate to 25%^[3].
PF-04217903 (40 mg/kg; p.o.; single administration; 12 h after MSU challenge) induces caspase-dependent neutrophil apoptosis and efferocytosis, alleviates joint inflammation, tissue damage and hyperalgesia, and promotes the expression of the pro-resolving protein annexin A1 in a mouse model of MSU-induced gouty arthritis^[5].
PF-04217903 (40 mg/kg; p.o.; single administration; 4 h after LPS (HY-D1056A1) challenge) promotes the resolution of inflammation in a mouse model of LPS-induced neutrophilic pleurisy by enhancing neutrophil apoptosis and efferocytosis^[5].
PF-04217903 (40 mg/kg; p.o.; single administration; 90 h after Zymosan (HY-W250113) challenge) enhances the efferocytosis capacity of macrophages in a zymosan-induced peritonitis mouse model^[5].
PF-04217903 (1-30 mg/kg; p.o.; once daily; 16 days; 0.15-15 mg/kg/d; s.c.; continuous infusion; 14 days; 0.3-10 mg/kg/d; p.o.; once daily; 4 days) exhibits potent, dose-dependent antitumor efficacy in MET-amplified GTL-16 xenograft models, with a tumor growth inhibition (TGI) rate of 100% at the oral dose of 30 mg/kg/d; its antitumor activity is directly associated with sustained inhibition of c-Met phosphorylation and downstream signaling pathways, as well as induction of tumor cell apoptosis^[6].
PF-04217903 (0.3-30 mg/kg; p.o.; once daily; for 10 consecutive days; 5-50 mg/kg; p.o.; once daily; for 3 consecutive days) exhibits dose-dependent antitumor efficacy in U87MG xenograft models with an HGF/c-Met autocrine loop, achieving a tumor growth inhibition (TGI) rate of 84% at an oral dose of 30 mg/kg/d. Its activity is mediated by inhibition of the c-Met signaling pathway, reduction of tumor cell proliferation, induction of apoptosis, anti-angiogenic effects, and decreased secretion of pro-angiogenic cytokines^[6].
As a monotherapy, PF-04217903 (50 mg/kg; p.o.; once daily; for 21 consecutive days) achieves a 40% TGI in a c-Met-overexpressing HT29 xenograft model, while RON shRNA alone achieves a 52% TGI; due to the blockade of the AKT signaling pathway and the induction of tumor cell apoptosis, the efficacy of the combination therapy is enhanced to a 77% TGI^[6].
PF-04217903 (1-30 mg/kg/d; p.o.; multiple administrations) dose-dependently reduces the plasma levels of pro-angiogenic factors IL-8 and VEGFA in mice bearing GTL-16 xenograft tumors^[6].