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 ofosteosarcoma. Herein, the design, synthesis, and structure-activity relationships (SAR) of novel pyrimidine-2,4-diamine derivativesthat selectively inhibit PDGFR alpha/beta kinases have been studied. The screening cascades revealed that7mwas the preferred compoundamong these derivatives, with IC50values of 2.4 and 0.9 nM for PDGFR alpha and PDGFR beta, respectively. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) experiment revealed that7mhas a substantial cytotoxic effect againstall osteosarcoma cancer cell lines;7malso displayed robust antitumor effects and low toxicity in a xenograft model. Additionally,7mshowed excellent bioavailability (F= 62.9%), suitable half-life (T1/2= 2.12 h), satisfactory metabolic stability, and weak CYP isoforminhibitory activity, suggesting that7mis a potential drug candidate for PDGFR-driven osteosarcoma.

Automated summary

This study investigated the design, synthesis, and structure-activity relationships of novel pyrimidine-2,4-diamine derivatives that selectively inhibit PDGFR alpha/beta kinases. Compound 7m showed the most promising activity against PDGFR alpha and beta, with low IC50 values. It also exhibited significant cytotoxic effects against osteosarcoma cancer cell lines, as well as robust antitumor effects and low toxicity in a xenograft model. The compound demonstrated favorable pharmacokinetic properties and showed potential as a drug candidate for PDGFR-driven osteosarcoma.