Thiazolidinones as Potential PGK1 Inhibitors for Treatment of Osteosarcoma Growth and Metastasis

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.