ABSTRACT
PF-06651600, a newly discovered potent JAK3-selective inhibitor, is highly efficacious at inhibiting γc cytokine signaling, which is dependent on both JAK1 and JAK3. PF-06651600 allowed the comparison of JAK3-selective inhibition to pan-JAK or JAK1-selective inhibition, in relevant immune cells to a level that could not be achieved previously without such potency and selectivity. In vitro, PF-06651600 inhibits Th1 and Th17 cell differentiation and function, and in vivo it reduces disease pathology in rat adjuvant-induced arthritis as well as in mouse experimental autoimmune encephalomyelitis models. Importantly, by sparing JAK1 function, PF-06651600 selectively targets γc cytokine pathways while preserving JAK1-dependent anti-inflammatory signaling such as the IL-10 suppressive functions following LPS treatment in macrophages and the suppression of TNFα and IL-1ß production in IL-27-primed macrophages. Thus, JAK3-selective inhibition differentiates from pan-JAK or JAK1 inhibition in various immune cellular responses, which could potentially translate to advantageous clinical outcomes in inflammatory and autoimmune diseases.
Subject(s)
Arthritis, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Janus Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Animals , Arthritis, Experimental/immunology , Disease Models, Animal , Drug Discovery , Encephalomyelitis, Autoimmune, Experimental/immunology , Humans , Interleukin-10/immunology , Interleukin-1beta/immunology , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/metabolism , Janus Kinase 3/metabolism , Macrophages/cytology , Macrophages/drug effects , Macrophages/immunology , Mice , Models, Molecular , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Th1 Cells/cytology , Th1 Cells/drug effects , Th1 Cells/immunology , Th17 Cells/cytology , Th17 Cells/drug effects , Th17 Cells/immunology , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Heparan sulfate proteoglycans (HSPGs) play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS) mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1α, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis.