The important role of glycogen synthase kinase 3 (GSK-3) in insulin resistance and glucose homeostasis makes it a potential diabetes drug target. Ace Therapeutics helps clients optimize and accelerate their preclinical GSK-3 inhibitor development programs using customized animal models and validated in vivo and in vitro testing. We provide end-to-end support from target validation to preclinical studies, enabling mechanistic understanding of drug candidates and PK optimization.

GSK-3 as a Therapeutic Target in Diabetes

Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine protein kinase that plays a central regulatory role in the insulin signaling pathway and Wnt signaling pathway. Its aberrant activation is closely related to the pathogenesis of type 2 diabetes mellitus (T2DM):

• Insulin resistance: GSK-3 inhibits glycogen synthase (GS) through phosphorylation, reducing hepatic glycogen synthesis and exacerbating hyperglycemia.
• β-cell dysfunction: GSK-3 hyperactivation inhibits the insulin gene transcription factor PDX1, leading to insufficient insulin secretion.
• Inflammation-driven: GSK-3 promotes adipose tissue inflammation through the NF-κB pathway, exacerbating insulin resistance.

GSK-3 inhibitors have emerged as a research hotspot for next-generation antidiabetic drugs by targeting either the ATP-binding domain or allosteric sites to restore glucose metabolic homeostasis, preserve β-cell function, and ameliorate insulin resistance.

Fig. 1 GSK-3 overactivity is implicated in numerous metabolic disorders. (Srivani, G.; et al., 2021)

Preclinical GSK-3 Inhibitor Development Services at Ace Therapeutics

GSK-3 target validation and mechanism study

• In vitro model:

Primary hepatocyte/adipocyte insulin sensitivity assay (GSK-3β activity assay)

Glucose-stimulated insulin secretion (GSIS) assay in human-derived beta cell lines (e.g. MIN6)

Kinase selectivity screening (GSK-3α/β vs. 300+ kinases such as CDK5, PKA, etc. Panel)

• Mechanism studies:

Phosphorylation proteomics (GSK-3 substrate network dynamics analysis)

Validation of Wnt/β-catenin and PI3K/Akt dual pathway regulation

Lead optimization services for GSK-3 inhibitors

• In vitro screening services

• ADMET prediction and optimization

AI-based molecular docking simulations (incorporating ATP pocket conformational dynamics)

Blood-brain barrier penetration assessment.

Preclinical GSK-3 Inhibitor Efficacy Evaluation Services

• Glucose homeostasis
• Glucose and insulin tolerance test
• High insulin normoglycemic/hyperglycemic clamps
• Lipid metabolism test
• Lipid tolerance test
• Standard hormone assays (insulin, glucagon, lipocalin, leptin, etc.)
• Inflammation (plasma cytokines)
• Tissue analysis (lipid, gene and protein expression)
• Histology, immunohistology and histopathology scoring

Advantages of Our Preclinical GSK-3 Inhibitor Development Services

• Comprehensive In vivo and in vitro diabetic models.
• Multi-dimensional technology platforms such as single-cell transcriptome, metabolic flux analysis, and molecular imaging.
• We provide one-stop service from target validation to preclinical testing.

Ace Therapeutics understands the challenges faced in GSK-3 inhibitor development. We are committed to accelerating your R & D program with customized solutions. Please contact us for more details.

References

1. Teli, D. M., and Anuradha K. G. Glycogen synthase kinase-3: A potential target for diabetes. Bioorganic & medicinal chemistry. 92 (2023): 117406.
2. Srivani, G.; et al. GSK-3 inhibitors as new leads to treat type-II diabetes. Current Drug Targets. 22.13 (2021): 1555-1567.
3. Maqbool, M. and Nasimul, H. GSK3 inhibitors in the therapeutic development of diabetes, cancer and neurodegeneration: past, present and future. Current pharmaceutical design. 23.29 (2017): 4332-4350.
4. Lemon, J. J., et al.; Role and Regulation of Glycogen Synthase Kinase-3 in Obesity-Associated Metabolic Perturbations. Kinases and Phosphatases. 2.3 (2024): 279-293.

• DGAT-Targeted Drug Development for Diabetes
• KKS-Targeted Drug Development for Diabetes
• FBPase-Targeted Drug Development for Diabetes
• MetAP2-Targeted Drug Development for Diabetes
• ANGPTL3-Targeted Drug Development for Diabetes
• GK-Targeted Drug Development for Diabetes
• AMPK-Targeted Drug Development for Diabetes
• 11β-HSD1-Targeted Drug Development for Diabetes
• PTP1B-Targeted Drug Development for Diabetes
• SGLT2-Targeted Drug Development for Diabetes
• Visfatin-Targeted Drug Development for Diabetes
• PEDF-Targeted Antidiabetic Drug Development Services
• FETUIN-A-Targeted Antidiabetic Drug Development Services
• ACRP30-Targeted Antidiabetic Drug Development Services

• Mouse Models
• Assay Kits
• Antibodies
• Cell Lines & Lysates
• Proteins & Peptides
• Inhibitors & Activators