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

Abstract

SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.

SOCS proteins in regulation of receptor tyrosine kinase signaling

“…Both FLT3 and KIT receptors are involved in rheumatoid arthritis, [100][101][102] and expression of several SOCS proteins has been reported to be deregulated in this disease [103,104], suggesting a possible role of SOCS proteins in RTK-mediated arthritis. Up-regulation of CIS and SOCS can be connected to rheumatoid arthritis [103,104].…”

JAK2-STAT3 Blockade by AG490 Suppresses Autoimmune Arthritis in Mice via Reciprocal Regulation of Regulatory T Cells and Th17 Cells

“…JAK2 inhibitors are classic therapeutics for myeloproliferative diseases because mutations of JAK2, which is associated with erythropoietin and tyrosine stromal lymphopoietin receptors, play a critical role (19)(20)(21). Recently, the JAK2 inhibitors CEP-33779 and SB1578 were investigated in an RA model (22,23). AG490 has been widely used as a JAK2 inhibitor in various settings, and it appears to specifically suppress JAK2/STAT3 signaling (24)(25)(26)(27).…”

Designed Macrocyclic Kinase Inhibitors

“…Further detailed information on the biological profiles, including cellular pharmacodynamic studies demonstrating intracellular inhibition of the kinases, of compounds 1, 2, and 3 are available. 77,90,91 …”

“…75,76 SB1578 (compound 2), discussed below, is a macrocycle that demonstrates c-FMS activity as well as potency against JAK2/FLT3 making it a unique candidate for small molecule RA therapy. 77 Evidence that the ERK5 (extracellular-signal-regulated kinase-5)-MEK5 (MAPK mitogen-activated protein kinase-5) signaling pathway is important in cancer disease progression is beginning to emerge. 78 Expression of MEK5 is up-regulated by constitutively active STAT3, important in breast cancer, 79 and increased expression of ERK5 is associated with poor survival in early breast cancer.…”

“…Efficacy of 1, 2, and 3 was assessed in a range of mouse models of cancer (Figure 5.17 and Figure 5.18). 77,90,91 Prior to conducting these experiments, dosing regimens for the compounds were explored and optimal schedules selected for each model for the duration of the experiment. The CDK2/FLT3/ JAK2 inhibitor 3 was evaluated in two human tumor xenograft mouse models.…”