Effects of the cFMS Kinase Inhibitor 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) in Normal and Arthritic Rats

Abstract

The cFMS (cellular homolog of the V-FMS oncogene product of the Susan McDonough strain of feline sarcoma virus) (Proc Natl Acad Sci U S A 83:3331-3335, 1986) kinase inhibitor 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) inhibits colony-stimulating factor (CSF)-1-induced monocyte growth and bone degradation in vitro and inhibits CSF-1 signaling through cFMS kinase in 4-day models in mice (Proc Natl Acad Sci U S A 102:16078, 2005). In the present study, the kinase selectivity of GW2580 was further characterized, and the effects of chronic treatment were evaluated in normal and arthritic rats. GW2580 selectively inhibited cFMS kinase compared with 186 other kinases in vitro and completely inhibited CSF-1-induced growth of rat monocytes, with an IC 50 value of 0.2 M. GW2580 dosed orally at 25 and 75 mg/kg 1 and 5 h before the injection of lipopolysaccharide inhibited tumor necrosis factor-␣ production by 60 to 85%, indicating a duration of action of at least 5 h. In a 21-day adjuvant arthritis model, GW2580 dosed twice a day (b.i.d.) from days 0 to 21, 7 to 21, or 14 to 21 inhibited joint connective tissue and bone destruction as assessed by radiology, histology and bone mineral content measurements. In contrast, GW2580 did not affect ankle swelling in the adjuvant model nor did it affect ankle swelling in a model where local arthritis is reactivated by peptidoglycan polysaccharide polymers. GW2580 administered to normal rats for 21 days showed no effects on tissue histology and only modest changes in serum clinical chemistry and blood hematology. In conclusion, GW2580 was effective in preserving joint integrity in the adjuvant arthritis model while showing minimal effects in normal rats.CSF-1 promotes the survival, proliferation, and differentiation of mononuclear phagocyte lineages and regulates the response of these lineages to inflammatory challenge. CSF-1 binding to its cell surface receptor triggers autophosphorylation by receptor cFMS (cellular homolog of the V-FMS oncogene product of the Susan McDonough strain of feline sarcoma virus) (Sacca et al., 1986) kinase and a cascade of cell signaling. cFMS kinase is the cellular homolog of the v-FMS oncogene product of the Susan McDonough strain of the feline sarcoma virus (Sacca et al., 1986). The ability of CSF-1 to promote the survival, proliferation, and differentiation of bone progenitor cells, monocytes, macrophages, and osteoclasts in vitro correlates with the expression of CSF-1 receptor in these cells (for review, see Chitu and Stanley, 2006). Mice without CSF-1 (Wiktor-Jedrzejczak et al., 1990, 1992b or its receptor (Dai et al., 2002) are osteopetrotic, deficient in several macrophage populations, show decreased TNF pro-

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

“…Within 21 days all mice had palpable tumors at the injection site. Xenografted mice were given liposomal clodronate (Lipclod) to selectively deplete phagocytic macrophages; GW2580 or AZD7507 ( Figure 5A) to inhibit the activation of CSF receptor 1 (CSFR1), thereby preventing monocyte differentiation into macrophages; or appropriate vehicle alone (41)(42)(43)(44). Tumors were isolated 8 hours after the final dose of each compound.…”

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

“…Clinical scores for the mice were determined for each of the four paws on study days [16][17][18][19][20][21][22][23][24][25][26][27][28]. The scores for all the four paws were given using the following criteria: 0, normal joints; 1, swelling in one digit or joint or minimal diffuse erythema; 2, swelling in two digits or joints or mild diffuse erythema; 3, swelling in three digits or joints or moderate diffuse erythema; 4, swelling in four digits or joints or marked diffuse erythema; 5, severe diffuse erythema and severe swelling of the entire paw and rigid joints.…”

“…Elevated levels of its ligand M-CSF are observed in the joints of RA patients, contributing to the development of macrophages and osteoclasts, which are the mediators of bone erosion (21)(22)(23)(24). Blockade of the M-CSF-c-Fms axis has been shown to inhibit the progression of arthritis in animal models indicating that it may play a pivotal role in the pathogenesis of RA (25,26). Signaling via FLT3 is also important for RA pathogenesis as FLT3-mediated signaling is essential for the in vivo differentiation of dendritic cells (DCs) (27).…”

Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases

“…17 CSF1R inhibitors, such as 2 and 3 (Figure 1), demonstrated efficacy against arthritis and inflammatory bone erosion in arthritic animal models. 18,19 Therefore, novel small molecule inhibitors targeting both FLT3 and CSF1R can be developed for either FLT3-ITD+ …”

“…17 CSF1R inhibitors, such as 2 and 3 (Figure 1), demonstrated efficacy against arthritis and inflammatory bone erosion in arthritic animal models. 18,19 Therefore, novel small molecule inhibitors targeting both FLT3 and CSF1R can be developed for either FLT3-ITD+ AML or cancer bone metastasis and rheumatoid arthritis. Synergy can also potentially be realized for autoimmune diseases by inhibiting both FLT3 and CSF1R simultaneously.…”