Glucokinase has been recognized as a promising antidiabetic target due to its pivotal role in glucose homeostasis. Ace Therapeutics specializes in providing comprehensive glucokinase (GK) agonist development services designed to help clients achieve breakthroughs in their antidiabetic drug development programs.

Introduction of Glucokinase and Glucokinase (GK) Agonists

Glucokinase (GK) is an attractive target for antidiabetic drugs. It acts as a glucose sensor, triggering a counter-regulatory response after a change in blood glucose levels to help normalize blood glucose. The activation of GK enhances the sensitivity of pancreatic β-cells to glucose, stimulating insulin secretion and thereby effectively reducing blood glucose levels. Simultaneously, GK activation suppresses hepatic gluconeogenesis, reducing hepatic glucose output and further improving liver glucose metabolism, which plays a positive role in diabetes management. Activation of GK induces glucose metabolism and lowers blood glucose levels, thereby treating type 2 diabetes. Glucokinase activators (GKAs) represent a promising class of antidiabetic agents with the potential to maintain glucose homeostasis. In the last few years, a new generation of GKAs has been reported, which can be categorized as bis-conjugated amides, mono-conjugated amides and other types based on differences in the molecular structure of GKAs.

GKA has a favorable safety profile and can be used in the conventional treatment of diabetes or as a temporary hypoglycemic agent for diabetic individuals with other co-morbidities. As a new target, this class of therapeutic agents is suitable for use in combination with other hypoglycemic agents to achieve better diabetes treatment.

Fig. 1 Effects of dorzagliatin on the pancreas. (Haddad, D.; et al., 2024)

Glucokinase (GK) Agonist Development Services at Ace Therapeutics

Early screening and optimization

We provide high-throughput screening services to identify compounds with potential GK agonist activity from a large library of compounds, and to further enhance their agonistic effect and selectivity through structural optimization. Our advanced technology and extensive expertise can help clients obtain a range of candidate compounds with high activity and selectivity.

• High-throughput screening (HTS): based on the mechanism of GK metastable activation, we use fluorescence resonance energy transfer (FRET) or enzyme coupling method to help clients quickly screen highly active candidate compounds.
• AI-assisted design: we combine molecular docking and deep learning models to optimize the GK binding, selectivity and metabolic stability of compounds.
• Structural biology support: we analyze the structure of GK-ligand complexes by X-ray crystallography to guide the rational design of key sites (e.g., metastable pockets).

In vitro functional validation

We validate the agonistic effect of the candidate compounds on GK and assess their effects on insulin secretion and glucose metabolism by enzyme activity assays and cellular assays.

• GK enzyme activity assay: we use recombinant human GK enzyme system to quantify the regulatory ability of the compounds.
• β-cell function modeling: INS-1 cell line, which exhibits robust insulin secretion responses to glucose stimulation. we assay the enhanced effect of glucose-stimulated insulin secretion (GSIS) by primary pancreatic islet cells or INS-1 cell line.
• Regulation of hepatic glycogen metabolism: regulation of hepatic glycogen metabolism: we utilize the HepG2 cell model to validate the inhibitory effects of GK agonists on glycogen synthesis and gluconeogenesis.

In vivo pharmacodynamic validation

We conduct in vivo experiments in diabetic animal models to evaluate the effects of candidate compounds on blood glucose control, insulin secretion, and glucose metabolism, along with pharmacokinetic (PK) and pharmacodynamic (PD) studies. These experiments will help us understand the efficacy and safety of the candidate compounds in vivo, providing support for subsequent preclinical research.

• Assessment of acute hypoglycemic effect: detection of glycemic changes (OGTT/IPGTT) after a single dose in type 2 diabetes model.
• Insulin sensitivity and histopathological evaluation: we use db/db mice or ZDF rats, we assess improvements in HbA1c, insulin sensitivity (HOMA-IR), and pancreatic/liver histopathology.

Advantages of Our Glucokinase (GK) Agonist Development Services

• We have a wealth of in vivo and in vitro diabetes models that can simulate different types of diabetes pathology, providing diverse options for the pharmacodynamic evaluation of GK agonists.
• We have a comprehensive drug analysis platform and advanced analytical equipment, capable of performing a wide range of analyses, including chemical, biological and pharmacodynamic analyses of drugs.
• We are also able to combine pharmacological and histological studies to comprehensively evaluate the efficacy and safety of drugs and provide support for drug development.

Ace Therapeutics leverages expert scientific guidance and extensive drug development experience in the field of diabetes, and is able to provide comprehensive antidiabetic drug development services to our clients. We look forward to working with more clients to promote the development and application of antidiabetic drugs. If interested, please feel free to contact us.

References

1. Ashcroft, F.M.; et al. Glucokinase activity in diabetes: too much of a good thing?. Trends in Endocrinology & Metabolism. 34.2 (2023): 119-130.
2. Haddad, D.; et al. New-generation glucokinase activators: potential game-changers in type 2 diabetes treatment. International Journal of Molecular Sciences. 25.1 (2024): 571.
3. Ren, Y.; et al. Glucokinase as an emerging anti-diabetes target and recent progress in the development of its agonists. Journal of Enzyme Inhibition and Medicinal Chemistry. 37.1 (2022): 606-615.

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