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.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

tau Proteins*/metabolism ; Glycogen Synthase Kinase 3 beta*/antagonists & inhibitors ; Glycogen Synthase Kinase 3 beta*/metabolism ; Alzheimer Disease*/drug therapy ; Alzheimer Disease*/metabolism ; Thiazoles*/pharmacology ; Thiazoles*/chemistry ; rho-Associated Kinases*/antagonists & inhibitors ; rho-Associated Kinases*/metabolism ; I-kappa B Kinase*/metabolism ; I-kappa B Kinase*/antagonists & inhibitors; Animals ; Humans ; Mice ; Neuroprotective Agents/pharmacology ; Neuroprotective Agents/chemistry ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/chemistry ; Cell Line ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/chemistry ; Microglia/drug effects ; Microglia/metabolism ; Nitric Oxide/metabolism ; Lipopolysaccharides ; Protein Aggregates/drug effects ; Neuroinflammatory Diseases/drug therapy ; Neuroinflammatory Diseases/metabolism

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 62 , a novel, remarkably potent, competitive GSK-3β inhibitor (IC 50 = 8 nM, K i = 2 nM) that also exhibits additional ROCK-1 inhibitory activity (IC 50 = 2.3 µM) 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.

Alzheimers Dement. 2021 Jan;17(1):115-124. (PMID: 33075193)
FEBS Lett. 2001 Oct 19;507(1):81-7. (PMID: 11682063)
Aging Cell. 2019 Oct;18(5):e13001. (PMID: 31287605)
Neurobiol Aging. 2020 May;89:41-54. (PMID: 31982202)
JAMA Neurol. 2022 Jan 1;79(1):13-21. (PMID: 34807243)
Acta Pharmacol Sin. 2017 Sep;38(9):1205-1235. (PMID: 28713158)
Adv Pharm Bull. 2023 Nov;13(4):688-700. (PMID: 38022801)
Int J Mol Sci. 2020 Jul 21;21(14):. (PMID: 32708302)
J Alzheimers Dis. 2015;45(1):75-88. (PMID: 25537011)
Cells. 2021 Sep 28;10(10):. (PMID: 34685563)
Int J Mol Sci. 2023 Apr 19;24(8):. (PMID: 37108703)
PLoS One. 2013 Nov 04;8(11):e78033. (PMID: 24223757)
Eur J Med Chem. 2022 Jun 5;236:114301. (PMID: 35390715)
J Neurosci. 2014 Sep 24;34(39):12982-99. (PMID: 25253847)
Int J Mol Sci. 2022 Aug 11;23(16):. (PMID: 36012242)
Front Mol Neurosci. 2022 Jan 21;14:792364. (PMID: 35126052)
Pharm Pat Anal. 2013 Jul;2(4):481-98. (PMID: 24237125)
J Neurochem. 2008 Mar;104(6):1433-9. (PMID: 18088381)
FEBS J. 2011 Jan;278(2):246-56. (PMID: 21126318)
Bioorg Med Chem Lett. 2015 May 1;25(9):1856-63. (PMID: 25845281)
Am J Manag Care. 2020 Aug;26(8 Suppl):S177-S183. (PMID: 32840331)
J Chem Theory Comput. 2021 Jul 13;17(7):4291-4300. (PMID: 34096718)
Curr Med Chem. 2022;29(27):4631-4697. (PMID: 35170406)
Nat Rev Neurosci. 2007 Sep;8(9):663-72. (PMID: 17684513)
Eur J Med Chem. 2019 Feb 15;164:448-470. (PMID: 30616053)
Trends Neurosci. 2011 Jun;34(6):316-25. (PMID: 21459462)
Int J Mol Sci. 2022 Oct 01;23(19):. (PMID: 36232909)
Int J Biol Sci. 2023 Aug 6;19(13):4181-4203. (PMID: 37705738)
Eur J Med Chem. 2024 Feb 5;265:116065. (PMID: 38160617)
J Clin Invest. 2013 Jan;123(1):224-35. (PMID: 23202730)
Protein Sci. 2021 Jan;30(1):70-82. (PMID: 32881101)
N Engl J Med. 2023 Jan 5;388(1):9-21. (PMID: 36449413)
Neurobiol Dis. 2010 Aug;39(2):156-68. (PMID: 20381617)
Bioorg Med Chem. 2017 Apr 1;25(7):2133-2147. (PMID: 28284870)
Semin Cancer Biol. 2019 Jun;56:12-24. (PMID: 29486318)
Neurobiol Dis. 2012 Jan;45(1):425-37. (PMID: 21945540)
Lancet. 2020 Aug 8;396(10248):413-446. (PMID: 32738937)
Mol Psychiatry. 2021 Oct;26(10):5481-5503. (PMID: 34456336)
Front Pharmacol. 2023 Jun 09;14:1161850. (PMID: 37361208)
Biomedicines. 2023 Sep 21;11(9):. (PMID: 37761028)
J Neurosci. 2013 Dec 4;33(49):19086-98. (PMID: 24305806)
Alzheimers Dement. 2022 Apr;18(4):700-789. (PMID: 35289055)
J Biol Chem. 2013 Jan 11;288(2):1295-306. (PMID: 23155049)
J Neurol Sci. 2005 Nov 15;238(1-2):31-9. (PMID: 16005902)
ChemMedChem. 2021 Apr 8;16(7):1116-1125. (PMID: 33513288)
J Neurochem. 2010 Nov;115(3):574-84. (PMID: 20456003)
Int J Nanomedicine. 2019 Jul 19;14:5541-5554. (PMID: 31410002)
Nat Rev Neurosci. 2020 Jan;21(1):21-35. (PMID: 31780819)
Neurobiol Dis. 2009 Sep;35(3):359-67. (PMID: 19523516)
Nat Protoc. 2006;1(5):2223-6. (PMID: 17406460)
Bioorg Chem. 2022 Sep;126:105875. (PMID: 35623141)
Int J Dev Neurosci. 2012 Oct;30(6):411-9. (PMID: 22906543)
J Neurochem. 2016 Aug;138(4):525-31. (PMID: 27246255)
Nat Rev Neurol. 2021 Mar;17(3):157-172. (PMID: 33318676)
FASEB J. 2023 Feb;37(2):e22778. (PMID: 36688823)
Int J Neuropsychopharmacol. 2012 Feb;15(1):77-90. (PMID: 21329555)
Arch Med Res. 2010 Apr;41(3):226-31. (PMID: 20682182)
Front Neurosci. 2019 May 15;13:472. (PMID: 31156366)
Assay Drug Dev Technol. 2009 Dec;7(6):560-72. (PMID: 20105026)
J Neurochem. 2011 Dec;119(6):1330-40. (PMID: 21992552)
Eur J Med Chem. 2022 May 5;235:114257. (PMID: 35367710)
Eur J Med Chem. 2021 Aug 5;220:113482. (PMID: 33906048)
Eur J Med Chem. 2018 Jan 20;144:517-528. (PMID: 29288948)
Protein Sci. 2018 Jan;27(1):14-25. (PMID: 28710774)
Bioorg Med Chem Lett. 2004 Jun 7;14(11):2817-22. (PMID: 15125939)

2019/34/E/NZ7/00090 National Science Centre Poland

Keywords: GSK-3β; IKK-β; ROCK-1; anti-inflammatory activity; neuroprotective properties Alzheimer’s disease

0 (tau Proteins)
EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
0 (Thiazoles)
EC 2.7.11.1 (rho-Associated Kinases)
EC 2.7.11.10 (I-kappa B Kinase)
0 (Neuroprotective Agents)
0 (Protein Kinase Inhibitors)
0 (Anti-Inflammatory Agents)
31C4KY9ESH (Nitric Oxide)
0 (Lipopolysaccharides)
0 (Protein Aggregates)

Date Created: 20240619 Date Completed: 20240619 Latest Revision: 20240708

20240708

PMC11173485

10.3390/molecules29112616

38893493