GSK3A and GSK3B are protein Ser/Thr kinases that are involved in the regulation of glycogen synthesis. GSK3B (GSK-3β) has been associated with the pathogenesis and progression of diseases including obesity, diabetes, cancer and Alzheimer's, and as a result pharmacological inhibition of this enzyme is an attractive therapeutic mechanism.

The GSK3 enzymes are essential for the development and function of T_reg [6] and T_eff cells [2,9,12]. In mice, conditional deletion of Gsk3a/b in T_reg cells leads to fatal multisystem autoimmune disease [6].

* Key recommended reading is highlighted with an asterisk

* Beurel E, Grieco SF, Jope RS. (2015) Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther, 148: 114-31. [PMID:25435019]

* Domoto T, Pyko IV, Furuta T, Miyashita K, Uehara M, Shimasaki T, Nakada M, Minamoto T. (2016) Glycogen synthase kinase-3β is a pivotal mediator of cancer invasion and resistance to therapy. Cancer Sci, 107 (10): 1363-1372. [PMID:27486911]

* Khan I, Tantray MA, Alam MS, Hamid H. (2017) Natural and synthetic bioactive inhibitors of glycogen synthase kinase. Eur J Med Chem, 125: 464-477. [PMID:27689729]

* Lauretti E, Dincer O, Praticò D. (2020) Glycogen synthase kinase-3 signaling in Alzheimer's disease. Biochim Biophys Acta Mol Cell Res, 1867 (5): 118664. [PMID:32006534]

Maqbool M, Mobashir M, Hoda N. (2016) Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer's disease. Eur J Med Chem, 107: 63-81. [PMID:26562543]

1. Berg S, Bergh M, Hellberg S, Högdin K, Lo-Alfredsson Y, Söderman P, von Berg S, Weigelt T, Ormö M, Xue Y et al.. (2012) Discovery of novel potent and highly selective glycogen synthase kinase-3β (GSK3β) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines. J Med Chem, 55 (21): 9107-19. [PMID:22489897]

2. Beurel E, Yeh WI, Michalek SM, Harrington LE, Jope RS. (2011) Glycogen synthase kinase-3 is an early determinant in the differentiation of pathogenic Th17 cells. J Immunol, 186 (3): 1391-8. [PMID:21191064]

3. Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Roxbee Cox L et al.. (2000) Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol, 7 (10): 793-803. [PMID:11033082]

4. Engler TA, Henry JR, Malhotra S, Cunningham B, Furness K, Brozinick J, Burkholder TP, Clay MP, Clayton J, Diefenbacher C et al.. (2004) Substituted 3-imidazo[1,2-a]pyridin-3-yl- 4-(1,2,3,4-tetrahydro-[1,4]diazepino-[6,7,1-hi]indol-7-yl)pyrrole-2,5-diones as highly selective and potent inhibitors of glycogen synthase kinase-3. J Med Chem, 47 (16): 3934-7. [PMID:15267232]

5. Ishiguro K, Shiratsuchi A, Sato S, Omori A, Arioka M, Kobayashi S, Uchida T, Imahori K. (1993) Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett, 325 (3): 167-72. [PMID:7686508]

6. Kandasamy M, Andrew HF, Raza IG, Mitchell R, Borsa M, Valvo S, Ali M, Kronsteiner B, Attar M, Clarke AJ. (2025) Glycogen synthase kinase-3 is essential for T_reg development and function. Cell Rep, 44 (9): 116256. [PMID:40938754]

7. Kunick C, Lauenroth K, Leost M, Meijer L, Lemcke T. (2004) 1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3 beta. Bioorg Med Chem Lett, 14 (2): 413-6. [PMID:14698171]

8. Marsell R, Sisask G, Nilsson Y, Sundgren-Andersson AK, Andersson U, Larsson S, Nilsson O, Ljunggren O, Jonsson KB. (2012) GSK-3 inhibition by an orally active small molecule increases bone mass in rats. Bone, 50 (3): 619-27. [PMID:22142634]

9. Ohteki T, Parsons M, Zakarian A, Jones RG, Nguyen LT, Woodgett JR, Ohashi PS. (2000) Negative regulation of T cell proliferation and interleukin 2 production by the serine threonine kinase GSK-3. J Exp Med, 192 (1): 99-104. [PMID:10880530]

10. Ring DB, Johnson KW, Henriksen EJ, Nuss JM, Goff D, Kinnick TR, Ma ST, Reeder JW, Samuels I, Slabiak T et al.. (2003) Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes, 52 (3): 588-95. [PMID:12606497]

11. Schmöle AC, Brennführer A, Karapetyan G, Jaster R, Pews-Davtyan A, Hübner R, Ortinau S, Beller M, Rolfs A, Frech MJ. (2010) Novel indolylmaleimide acts as GSK-3beta inhibitor in human neural progenitor cells. Bioorg Med Chem, 18 (18): 6785-95. [PMID:20708937]

12. Taylor A, Harker JA, Chanthong K, Stevenson PG, Zuniga EI, Rudd CE. (2016) Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8(+) Cytolytic T Cell Responses. Immunity, 44 (2): 274-86. [PMID:26885856]