Connecting GSK-3β Inhibitory Activity with IKK-β or ROCK-1 Inhibition to Target Tau Aggregation and Neuroinflammation in Alzheimer's Disease-Discovery, In Vitro and In Cellulo Activity of Thiazole-Based Inhibitors

• Published in: Molecules (Basel, Switzerland) Switzerland), 2024-06, Vol.29 (11), p.2616
• Main Authors: Góral, Izabella, Wichur, Tomasz, Sługocka, Emilia, Godyń, Justyna, Szałaj, Natalia, Zaręba, Paula, Głuch-Lutwin, Monika, Mordyl, Barbara, Panek, Dawid, Więckowska, Anna
• Format: Article
• Language: English
• Subjects: Advertising executives; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; anti-inflammatory activity; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Cell Line; Cytokines; Dementia; Development and progression; Diseases; Germany; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - metabolism; GSK-3β; Humans; I-kappa B Kinase - antagonists & inhibitors; I-kappa B Kinase - metabolism; IKK-β; Instrument industry; Kinases; Ligands; Lipopolysaccharides; Massachusetts; Memory; Mice; Microglia - drug effects; Microglia - metabolism; Neuroinflammatory Diseases - drug therapy; Neuroinflammatory Diseases - metabolism; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; neuroprotective properties Alzheimer’s disease; Nitric oxide; Nitric Oxide - metabolism; Pharmaceutical industry; Phosphorylation; Poland; Protein Aggregates - drug effects; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proteins; Rankings; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism; ROCK-1; tau Proteins - metabolism; Thiazoles - chemistry; Thiazoles - pharmacology; Tumor necrosis factor-TNF; United States
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29112616

GSK-3β, IKK-β, and ROCK-1 kinases are implicated in the pathomechanism of Alzheimer's disease due to their involvement in the misfolding and accumulation of amyloid β (Aβ) and tau proteins, as well as inflammatory processes. Among these kinases, GSK-3β plays the most crucial role. In this study, we present compound , a novel, remarkably potent, competitive GSK-3β inhibitor (IC = 8 nM, K = 2 nM) that also exhibits additional ROCK-1 inhibitory activity (IC = 2.3 µM) and demonstrates anti-inflammatory and neuroprotective properties. Compound effectively suppresses the production of nitric oxide (NO) and pro-inflammatory cytokines in the lipopolysaccharide-induced model of inflammation in the microglial BV-2 cell line. Furthermore, it shows neuroprotective effects in an okadaic-acid-induced tau hyperphosphorylation cell model of neurodegeneration. The compound also demonstrates the potential for further development, characterized by its chemical and metabolic stability in mouse microsomes and fair solubility.