Discovery of Potent and Orally Bioavailable Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for the Treatment of Osteosarcoma

Platelet-derived
growth factor receptors (PDGFRs) are now considered
promising targets for the treatment of osteosarcoma. Herein, the design,
synthesis, and structure–activity relationships (SAR) of novel
pyrimidine-2,4-diamine derivatives that selectively inhibit PDGFRα/β
kinases have been studied. The screening cascades revealed that 7m was the preferred compound among these derivatives, with
IC50 values of 2.4 and 0.9 nM for PDGFRα and PDGFRβ,
respectively. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT) experiment revealed that 7m has a substantial
cytotoxic effect against all osteosarcoma cancer cell lines; 7m also displayed robust antitumor effects and low toxicity
in a xenograft model. Additionally, 7m showed excellent
bioavailability (F = 62.9%), suitable half-life (T1/2 = 2.12 h), satisfactory metabolic stability,
and weak CYP isoform inhibitory activity, suggesting that 7m is a potential drug candidate for PDGFR-driven osteosarcoma.