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.