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Due to unknown pathogenesis and unidentified drug target, no drug for the treatment of osteosarcoma (OS) has been launched to the market. Herein, thiazolidinone 1a was discovered as a hit compound by phenotypic screening with an in-house patrimonial collection of structural diversity. The following SAR (Structure-Activity Relationship) study affords the final water-soluble lead compound (R)-8i as a potential inhibitor for the proliferation of OS cells by the modulation of solubility of the compounds with remarkable cellular potency (IC50 = 21.9 nM for MNNG/HOS cells) and in vivo efficacy (52.9% inhibition OS growth in mice), as well as pharmacokinetic properties. (R)-8i also significantly suppresses OS cell migration in vitro and showed to be well-tolerated. Our preliminary investigation shows that the effects of (R)-8i are not dependent on p53 and myoferlin (MYOF). These results suggest that (R)-8i might be a potential drug candidate for OS treatment.
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