A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation

Abstract

Autoantibodies and the immunoreceptors to which they bind can contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). Spleen Tyrosine Kinase (Syk) is a non-receptor tyrosine kinase with a central role in immunoreceptor (FcR) signaling and immune cell functionality. Syk kinase inhibitors have activity in antibody-dependent immune cell activation assays, in preclinical models of arthritis, and have progressed into clinical trials for RA and other autoimmune diseases. Here we describe the characterization of a novel triazolopyridine-based Syk kinase inhibitor, CC-509. This compound is a potent inhibitor of purified Syk enzyme, FcR-dependent and FcR-independent signaling in primary immune cells, and basophil activation in human whole blood. CC-509 is moderately selective across the kinome and against other non-kinase enzymes or receptors. Importantly, CC-509 was optimized away from and has modest activity against cellular KDR and Jak2, kinases that when inhibited in a preclinical and clinical setting may promote hypertension and neutropenia, respectively. In addition, CC-509 is orally bioavailable and displays dose-dependent efficacy in two rodent models of immune-inflammatory disease. In passive cutaneous anaphylaxis (PCA), CC-509 significantly inhibited skin edema. Moreover, CC-509 significantly reduced paw swelling and the tissue levels of pro-inflammatory cytokines RANTES and MIP-1α in the collagen-induced arthritis (CIA) model. In summary, CC-509 is a potent, moderately selective, and efficacious inhibitor of Syk that has a differentiated profile when compared to other Syk compounds that have progressed into the clinic for RA.

TAS05567, a Novel Potent and Selective Spleen Tyrosine Kinase Inhibitor, Abrogates Immunoglobulin-Mediated Autoimmune and Allergic Reactions in Rodent Models

“…In comparison, R406 at 500 nM (approximately 40 times its IC 50 for Syk) showed .70% inhibition of 43 of the 192 kinases. During clinical trials of fostamatinib in patients with RA, adverse events such as hypertension, neutropenia, and anemia were considered to be related to inhibition of VEGFR2 and JAK2 (Baluom et al, 2013;Ferguson et al, 2016). Accordingly, the IC 50 values of TAS05567 and R406 were determined for four selected kinases, including VEGFR2 and JAK2.…”

“…Indeed, several ATP-competitive Syk inhibitors, notably fostamatinib (Rigel Pharmaceuticals), have already been evaluated in clinical trials performed in patients with autoimmune diseases, including RA and ITP (Bajpai, 2009). Even though fostamatinib was efficacious against chronic refractory ITP (Podolanczuk et al, 2009), it is unclear whether inhibition of Syk activity specifically contributed to the clinical response and adverse events observed in the clinical trials, as this drug inhibits several kinases, including vascular endothelial growth factor receptor (VEGFR) 2 and Janus kinase (JAK) 2 (Braselmann et al, 2006;Ferguson et al, 2016). Another Syk inhibitor (GS-9973, entospletinib, Gilead Sciences) has been developed for the treatment of leukemia, but it inhibits multiple protein kinases within 100-fold of its median inhibitory concentration (IC 50 ) value for Syk (Burke et al, 2014).…”

Mast Cells in Allergy: The Potential Molecular Targets in the Upstream Signalling Pathways

“…Recent studies reported that Syk inhibitors, including fostamatinib, PRT062607 and R343, were being withdrawn as a result of not passing phase two clinical trials (Lusková and Dráber, 2004;Braselmann et al, 2006;Riccaboni et al, 2010;Simmons, 2013;Weinblatt et al, 2013). Recently, one novel Syk inhibitor known as CC-509 has been reported to potentially inhibit IgE-mediated -hexosaminidase from LAD2 cells (IC50 = 0.22 μM) (Ferguson et al, 2016). Another inhibitor known as NVP-QAB205 has also been reported to inhibit both histamine release and the production of LTC4/LTD4/LTE4 and PGD2 in MCs collected from patients with nasal polyposis who underwent sinus surgery (Ali et al, 2008).…”

Investigative Drugs for Rheumatoid Arthritis: Novel Targets

“…Most recently, Ferguson et al [20] developed a novel triazolopyridine-based SyK inhibitor, CC-509. CC-509 was shown to be moderately selective for SyK and showed only modest activity towards the "kinase domain receptor" (KDR) and JAK2.…”