LCC18, a benzamide‐linked small molecule, ameliorates IgA nephropathy in mice

Abstract

IgA nephropathy (IgAN), an immune complex‐mediated process and the most common primary glomerulonephritis, can progress to end‐stage renal disease in up to 40% of patients. Accordingly, a therapeutic strategy targeting a specific molecular pathway is urgently warranted. Aided by structure characterisation and target identification, we predicted that a novel ring‐fused 6‐(2,4‐difluorophenyl)‐3‐(3‐(trifluoromethyl)phenyl)‐2H‐benzo[e][1,3]oxazine‐2,4(3H)‐dione (LCC18) targets the NLRP3 inflammasome, which participates in IgAN pathogenesis. We further developed biomarkers for the disease. We used two complementary IgAN models in C57BL/6 mice, involving TEPC‐15 hybridoma‐derived IgA, and in gddY mice. Moreover, we created specific cell models to validate therapeutic effects of LCC18 on IgAN and to explain its underlying mechanisms. IgAN mice benefited significantly from treatment with LCC18, showing dramatically improved renal function, including greatly reduced proteinuria and renal pathology. Mechanistic studies showed that the mode of action specifically involved: (1) blocking of the MAPKs/COX‐2 axis‐mediated priming of the NLRP3 inflammasome; (2) inhibition of ASC oligomerisation and NLRP3 inflammasome assembly by inhibiting NLRP3 binding to PKR, NEK7 and ASC; and (3) activation of autophagy. LCC18 exerts therapeutic effects on murine IgAN by differentially regulating NLRP3 inflammasome activation and autophagy induction, suggesting this new compound as a promising drug candidate to treat IgAN. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

NEK7-Mediated Activation of NLRP3 Inflammasome Is Coordinated by Potassium Efflux/Syk/JNK Signaling During Staphylococcus aureus Infection

“…In agreement with the in vivo results, our in vitro data showed that the expression of NEK7 in both types of macrophages was decreased during S. aureus infection, simultaneously, the formation of NEK7 and NLRP3 complexes was increased ( Figures 2A–C ). Consistently, some studies reported that the expression of NEK7 was decreased with the enhanced interaction of NEK7-NLRP3 under the stimulation of LPS and ATP ( 25 ), LPS and cytotoxic necrosis factor (CNF1) ( 26 ) or LPS and IgA ICs ( 27 ). Furthermore, S. aureus infection-induced expression of NLRP3 inflammasome-associated molecules were significantly decreased by NEK7-siRNA pretreatment ( Figures 2D–F ), suggesting that NEK7 participated in NLRP3 inflammasome activation.…”

Multi-Omics Identification of Genetic Alterations in Head and Neck Squamous Cell Carcinoma and Therapeutic Efficacy of HNC018 as a Novel Multi-Target Agent for c-MET/STAT3/AKT Signaling Axis

“…Trifluoromethylphenyl is a key ingredient that contributes to the bioactivity of a number of clinical medications, including nilotinib (a tyrosine kinase inhibitor with antineoplastic activity), fluoxetine (an anti-depressant, anti-obsessional, anti-anxiety, and immune-modulating agent), and sorafenib (an RAF/MEK/ERK inhibitor with antineoplastic activity). Niclosamide is a versatile drug with a track record of success in the treatment of a number of illnesses, including cancer, oxidative stress, infections, metabolic disorders, and inflammation [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. A scaffold-hopping ( Figure 2 ) of these bioactive natural chemicals (flavones and isoflavones), biphenyl, trifluoromethyl, and niclosamide led to the development of a novel multi-target small molecule in the present study: 6-(2, 4-difluorophenyl)-3-(3-(trifluoromethyl) phenyl)-2H-benzol (e) (1, 3) oxazine-2, 4 (3H)-dione (HNC018).…”

The Role of NLRP3 Inflammasome in IgA Nephropathy

“…In addition, a recent study in Taiwan found that compound K inhibited the activation of the renal NLRP3 inflammasome in treated IgAN mice, and increased induction of autophagy in IgA-IC-primed macrophages, revealing the protective mechanisms of autophagy in IgAN [ 26 ]. In their later study in vitro and vivo, LCC18, a benzamide-linked small molecule, was found to improve renal function and reduce proteinuria in IgAN by blocking the priming of the NLRP3 inflammasome and inhibiting its activation through autophagy induction, further confirming the positive effect of autophagy in IgAN [ 38 ].…”