Identification and study of new NF‐κB‐inducing kinase ligands derived from the imidazolone scaffold

• Published in: Archiv der Pharmazie (Weinheim) 2025-01, Vol.358 (1), p.e2400614-n/a
• Main Authors: Maqueda‐Zelaya, Francisco, Valiño‐Rivas, Lara, Milián, Ana, Gutiérrez, Sara, Aceña, José Luis, Garcia‐Marin, Javier, Sánchez‐Niño, Mª Dolores, Vaquero, Juan J., Ortiz, Alberto
• Format: Article
• Language: English
• Subjects: Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; imidazolone; Kidney diseases; Ligands; MAP3K14; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-kappaB-Inducing Kinase; NF‐κB‐inducing kinase; NIK; noncanonical pathway; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Renal Insufficiency, Chronic - drug therapy; Signal Transduction - drug effects; Structure-Activity Relationship
• ISSN: 0365-6233; 1521-4184; 1521-4184
• DOI: 10.1002/ardp.202400614

Chronic kidney disease (CKD) is a growing health concern, projected to be a major cause of death by 2040, due to an increasing risk of acute kidney injury (AKI). Systems biology‐derived data suggest that the unmet need for an orally available drug to treat AKI and improve CKD outcomes may be addressed by targeting kidney inflammation and, specifically, nuclear factor κB‐inducing kinase (NIK), a key signaling molecule that activates the noncanonical nuclear factor κB (NF‐κB) pathway. We have prepared and identified a small family of imidazolone derivatives that bind NIK and inhibit the noncanonical NF‐κB activation pathway. The introduction of heterocyclic substituents in position 2 of the imidazolone core provides compounds with affinity against human NIK. Three candidates, with best affinity profile, were tested in phenotypic experiments of noncanonical NF‐κB activation, confirming that the derivative bearing the 4‐pyridyl ring can inhibit the processing of NFκB p100 to NFkB2 p52, which is NIK‐dependent in cultured kidney tubular cells. Finally, exhaustive docking calculations combined with molecular dynamics studies led us to propose a theoretical binding mode and rationalize affinity measures, in which the aminopyridine motif is a key anchoring point to the hinge region thanks to several hydrogen bonds and the interaction of heterocyclic rings in position 2 with Ser476 and Lys482. Our result will pave the way for the development of potential drug candidates targeting NIK in the context of CKD. A new family of NF‐κB‐inducing kinase (NIK) ligands bearing an imidazolone moiety were synthesized. The best compound showed a dose‐dependent inhibition of p100 to p50 processing in cellular assays, a key step in nuclear factor κB (NF‐κB) activation. Based on computational techniques, a plausible binding mode is proposed.