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

被引：2

作者：

Goral, Izabella ^{[1
,2
]}

Wichur, Tomasz ^{[1
]}

Slugocka, Emilia ^{[1
,2
]}

Godyn, Justyna ^{[1
]}

Szalaj, Natalia ^{[1
]}

Zareba, Paula ^{[1
]}

Gluch-Lutwin, Monika ^{[3
]}

Mordyl, Barbara ^{[3
]}

Panek, Dawid ^{[1
]}

Wieckowska, Anna ^{[1
]}

机构：

[1] Jagiellonian Univ Med Coll, Fac Pharm, Dept Physicochem Drug Anal, 9 Med St, PL-30688 Krakow, Poland

[2] Jagiellonian Univ Med Coll, Doctoral Sch Med & Hlth Sci, 16 Lazarza St, PL-31530 Krakow, Poland

[3] Jagiellonian Univ Med Coll, Fac Pharm, Dept Pharmacobiol, Fac Pharm, 9 Med St, PL-30688 Krakow, Poland

来源：

MOLECULES | 2024年 / 29卷 / 11期

关键词：

GSK-3; beta; IKK-beta; ROCK-1; anti-inflammatory activity; neuroprotective properties Alzheimer's disease; PHOSPHORYLATION; PATHOLOGY; NEURODEGENERATION; ACTIVATION; HYPOTHESIS; POTENT; MODEL;

D O I：

10.3390/molecules29112616

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

GSK-3 beta, IKK-beta, and ROCK-1 kinases are implicated in the pathomechanism of Alzheimer's disease due to their involvement in the misfolding and accumulation of amyloid beta (A beta) and tau proteins, as well as inflammatory processes. Among these kinases, GSK-3 beta plays the most crucial role. In this study, we present compound 62, a novel, remarkably potent, competitive GSK-3 beta inhibitor (IC50 = 8 nM, Ki = 2 nM) that also exhibits additional ROCK-1 inhibitory activity (IC50 = 2.3 mu M) and demonstrates anti-inflammatory and neuroprotective properties. Compound 62 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.

引用

页数：32