Syk inhibitors with high potency in presence of blood

Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

“…Using both immunostaining and PCR analysis, we identified prominent T-cell infiltration and activation within the allograft which was unaffected by CC0482417 treatment. One issue that complicates the understanding of Syk function is that the Syk inhibitor drug used in most animal studies, fostamatinib, is non-selective and inhibits 14 other kinases more potently than Syk, including Jak2 and ZAP70 which play critical roles in T-cell activation (Davis et al 2011;Currie et al 2014;Thoma et al 2014). However, a role for Syk in early thymocyte development has been described, although this does not prevent the development of mature T cells (Chan et al 1994;Palacios & Weiss 2007), and the abnormal T cells present in systemic lupus erythematosus and in T cell lymphomas can utilise Syk signalling (Feldman et al 2008;Grammatikos et al 2013).…”

“…However, a role for Syk in early thymocyte development has been described, although this does not prevent the development of mature T cells (Chan et al 1994;Palacios & Weiss 2007), and the abnormal T cells present in systemic lupus erythematosus and in T cell lymphomas can utilise Syk signalling (Feldman et al 2008;Grammatikos et al 2013). One issue that complicates the understanding of Syk function is that the Syk inhibitor drug used in most animal studies, fostamatinib, is non-selective and inhibits 14 other kinases more potently than Syk, including Jak2 and ZAP70 which play critical roles in T-cell activation (Davis et al 2011;Currie et al 2014;Thoma et al 2014). Indeed, the active metabolite of fostamatinib, R406, was originally described as having activity against IL-2-induced T-cell proliferation and IL-4-induced B-cell activation, indicating blockade of JAK/STAT signalling (Braselmann et al 2006).…”

Orally bioavailable Syk inhibitors with activity in a rat PK/PD model

“…14 We were pleased to learn that these compounds are equipotent to our development candidate 4 in enzymatic, cellular and blood assays (Table 2). 10 Notably, thiazoles (7,8) and isothiazoles (9,10) were equally active. We obtained crystal structures of representative compounds 11 (thiazole; Compounds 7-10 exhibited good solubility (> 1 mM at pH 6.8), medium permeability (log PAMPA from -4.9 to -5.2 10 -6 cm/s), medium plasma protein binding (human: 80-90%) and acceptable stability against rat liver microsomes (half-life from 34-82 min).…”

“…We stopped early work on Syk inhibitors sharing the binding mode of 2 because of insurmountable PK issues. 8 Furthermore, we had to abandon the promising Syk inhibitor 4 (see Figure 1 and Table 1) due to liver findings and a hERG flag leading to an insufficient therapeutic index for autoimmune indications. 9 In rat compound 4 exhibited >100 fold higher exposure in liver and kidney compared to blood.…”

Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs

“…In detail, the molecular interactions between the two SH2 domains and the ITAMs of receptors allow SYK to be phosphorylated on interdomains A and B and at the C terminus via auto‐ and/or transphosphorylation by the Src‐family tyrosine kinase Lyn, which is directly linked to the activation of the kinase domain and to substrate interaction . Activated SYK phosphorylates a number of substrates and participates in the activation of various signals and pathways, such as Ca 2+ /protein kinase C (PKC) signaling, RAS homolog (RHO) family/protein tyrosine kinase 2 (PYK2)‐mediated cytoskeletal rearrangements, reactive oxygen species (ROS) production/phagocytosis, phosphoinositide 3‐kinase (PI3K)‐mediated TeC family/AKT signaling pathways, Ras/extracellular signal‐regulated kinase (ERK) pathways, phospholipase Cg (PLCg)/Ca 2+ ‐nuclear factor of activated T cells (NFAT) pathways, Vav‐1/RAC pathways, and the nuclear factor κB (IKK/NF‐κB) pathway . SYK activation in immune cells results in cytokine release, differentiation, proliferation, ROS production, cytoskeletal rearrangements, and survival, depending on the cell type and its distinct set of effector molecules .…”