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Thiazolidinones as Potential PGK1 Inhibitors for Treatment of Osteosarcoma Growth and Metastasis
Xuwen Chen1, Meng Li1,2, Zongjing Hu1
1Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
Abstract:
Osteosarcoma is one of the malignant bone tumors in children and adolescents. Due to unclear pathogenesis and lack of identified drug targets, there has been limited progress in developing targeted therapies in the past 50 years. Here, we conducted an extensive structure-activity relationship study of thiazolidinone inhibitors by phenotypic screening to discover compound 60, which demonstrates potent cellular activity in MNNG-HOS cells (IC50 = 0.072 μM) and exhibits significant antitumor effect (61.6% inhibition of OS growth in vivo) and low toxicity. Compound 60 also shows a good pharmacokinetic profile with a bioavailability F = 80% following intraperitoneal administration. The photo-cross-linking probes were designed and synthesized from 60 to identify PGK1 as a potential target of 60 using an activity-based protein profiling strategy. Western blot, shRNA knockdown, wound healing assays, cellular thermal shift assays, cell colony formation, and transwell assays suggest that 60 is a promising PGK1 inhibitor for OS treatment.
Insights
A novel thiazolidinone compound, 60, shows potent activity against osteosarcoma (OS) by inhibiting PGK1. This compound demonstrates significant antitumor effects with low toxicity and good bioavailability, offering a promising new therapeutic avenue for this bone cancer.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Osteosarcoma (OS) is a prevalent malignant bone tumor in children and adolescents with limited therapeutic advancements due to unclear pathogenesis and a lack of identified drug targets.
- The development of targeted therapies for OS has been significantly hindered over the past 50 years, necessitating the exploration of novel therapeutic strategies.
Purpose of the Study:
- To discover and characterize novel thiazolidinone inhibitors for osteosarcoma treatment.
- To identify the molecular target of the lead compound and evaluate its efficacy and safety profile.
Main Methods:
- Extensive structure-activity relationship (SAR) studies and phenotypic screening were employed to identify potent thiazolidinone inhibitors.
- Photo-cross-linking probes derived from the lead compound were synthesized for target identification using activity-based protein profiling (ABPP).
- In vitro assays (MNNG-HOS cells) and in vivo studies in mice, along with pharmacokinetic assessments, were conducted to evaluate efficacy, toxicity, and bioavailability.
Main Results:
- Compound 60 exhibited potent cellular activity against MNNG-HOS cells (IC50 = 0.072 μM) and demonstrated significant in vivo antitumor effects (61.6% inhibition of OS growth) with low toxicity.
- Compound 60 displayed favorable pharmacokinetic properties, including 80% bioavailability after intraperitoneal administration.
- Activity-based protein profiling identified phosphoglycerate kinase 1 (PGK1) as a potential molecular target of compound 60.
Conclusions:
- Compound 60 is a potent inhibitor of PGK1 and shows significant promise as a therapeutic agent for osteosarcoma treatment.
- The identified compound exhibits a favorable efficacy, safety, and pharmacokinetic profile, warranting further investigation for clinical application in osteosarcoma.
- Targeting PGK1 with novel inhibitors like compound 60 represents a viable strategy to overcome the limitations of current osteosarcoma therapies.
