Identification of two potential glycogen synthase kinase 3β inhibitors for the treatment of osteosarcoma

Area of Science:

• Oncology
• Pharmacology
• Computational Biology

Background:

• Osteosarcoma is a prevalent adolescent bone cancer with high mortality.
• Glycogen synthase kinase 3β (GSK3β) is a validated therapeutic target for osteosarcoma.
• Developing novel GSK3β inhibitors is crucial for advancing osteosarcoma treatment.

Purpose of the Study:

• To identify novel, effective GSK3β inhibitors using bioinformatics approaches.
• To evaluate the potential of identified compounds as anti-osteosarcoma agents.

Main Methods:

• Bioinformatic screening of the ZINC Drug Database for GSK3β inhibitors.
• Molecular docking, molecular dynamic simulations, and MM/GBSA for inhibitor identification.
• In vitro kinase inhibition assays and cell proliferation assays on osteosarcoma cell lines.

Main Results:

• Two compounds, ZINC08383479 and ZINC08441251, were identified as potent GSK3β inhibitors.
• Both compounds demonstrated significant inhibition of GSK3β kinase activity in vitro.
• ZINC08383479 and ZINC08441251 effectively inhibited proliferation in U2OS and MG63 osteosarcoma cell lines.

Conclusions:

• ZINC08383479 and ZINC08441251 represent promising novel inhibitors of GSK3β.
• These compounds show potential for developing new therapeutic strategies against osteosarcoma.
• The study provides a foundation for designing more potent GSK3β inhibitors for osteosarcoma treatment.