Luxeptinib disables NLRP3 inflammasome-mediated IL-1β release and pathways required for secretion of inflammatory cytokines IL-6 and TNFα

Abstract

Luxeptinib (CG-806) is an orally bioavailable multikinase inhibitor with nanomolar potency against select clusters of kinases including the BTK, FLT3, TRK, STE/MAPK and aurora kinase clusters. It is cytotoxic to primary malignant cells obtained from patients with AML, ALL, and CLL at lower concentrations than other BTK and FLT3 inhibitors, and has activity in AML and lymphoma xenografts at concentrations attainable in patients. Exposure of macrophages and monocytes to endotoxin triggers the release of IL-1β through activation of the NLRP3 inflammasome and IL-6 and TNFα through transcriptional up-regulation. These cytokines are key components of the innate immune signaling network that plays a central role in the pathogenesis of multiple human diseases including cancer. Drugs that concurrently inhibit proliferation and inflammatory signaling pathways may provide better therapeutic efficacy. The aim of this study was to determine the extent to which luxeptinib interferes with the release of IL-1β, IL-6 and TNFα from THP-1 monocytes and bone marrow-derived macrophages following endotoxin exposure and priming of the NLRP3 inflammasome. Luxeptinib inhibited the release of all 3 cytokines from THP-1 monocytes and macrophages at concentrations of 0.1 µM and above. Investigation of the mechanism disclosed that luxeptinib does not inhibit the assembly of the NLRP3 inflammasome but disables its ability to cleave and activate caspase-1 that is required for IL-1β release. It also inhibits the kinases p38MAPK, ERK1/2, SAPK/JNK and activation of transcription factor NF-κBp65 with a concentration profile similar to its inhibition of cytokine release. ImplicationsThe ability of luxeptinib to inhibit the NLRP3-mediated release of IL-1β and pathways involved in the release of IL-6 and TNFα at concentrations which are well-tolerated in patients makes it a candidate for the treatment of inflammatory diseases and inflammation-associated resistance in cancer.