Discovery of Potent and Balanced Dual RIPK2 and 3 Inhibitors as a New Strategy for the Treatment of Inflammatory Bowel Diseases

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 25, 2025

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) and RIPK3 have been demonstrated to be promising targets for treating multiple inflammatory diseases, including bowel diseases (IBDs). Due the complexity of IBD pathogenesis, on basis synergy strategies, we herein describe discovery optimization a series N,7-diaryl-quinazolin-4-amine derivatives as dual RIPK2 inhibitors. Based step-by-step process involving three rounds structural modifications, compound 29 was identified most one, exhibiting balanced potency against (IC50 = 12 nM) 18 nM), well demonstrating good selectivity over other targets. Further biological evaluation confirmed that could bind directly RIPK3, effectively suppressing NOD-induced cytokine production cellular necroptosis. Notably, displayed significant therapeutic effects in DSS-induced colitis mouse model, with no detectable toxicity, indicating its potential RIPK2/RIPK3 inhibitors treatment IBD.

Language: Английский

Impact of liquid–liquid phase separation- and immune-related gene signatures on multiple myeloma prognosis: focus on DDX21 and EZH2

Hematology, Journal Year: 2024, Volume and Issue: 30(1)

Published: Dec. 23, 2024

Objective: Liquid–liquid phase separation (LLPS) may affect the therapeutic sensitivity of multiple myeloma (MM). This study aimed to identify LLPS-related genes with MM prognostic values and confirm their effects on tumor progression.

Language: Английский