۱,۳,۵-triazines inhibit osteosarcoma and avert lung metastasis in a patient-derived orthotopic xenograft mouse model with favorable pharmacokinetics

Objective(s): Osteosarcoma is a major solid malignant tumor of bone, possessing significant burden on healthcare due to non-availability of specific anticancer agents. The current study was conducted to identify novel ۱,۳,۵-triazine derivatives against osteosarcoma. Materials and Methods: The compounds were synthesized in a straight-forward two-step reaction and subsequently tested against PI۳K and mTOR kinase and anticancer activity against osteosarcoma cells (MG-۶۳, U۲-OS, and Saos-۲). The effect of the most potent compound was evaluated on apoptosis and cell phase of Saos-۲ cells. The pharmacological activity was further established in the patient-derived orthotopic xenograft (PDOX) mouse model. Results: The developed compounds ۸ (a-f) showed significant inhibitory activities against PI۳K, mTOR, and OS cells. Among the tested series, compound ۸a showed highly potent PI۳K/mTOR inhibitory activity with significant anticancer activity against Saos-۲ cells compared with Imatinib as standard. It also induces apoptosis and causes G۲/M arrest in Saos-۲ cells. Compound ۸a significantly improved body weight, reduced tumor volume, and inhibited lung metastasis in athymic nude mice in a PDOX mouse model. It also showed optimal pharmacokinetic parameters in SD rats. Conclusion: In summary, ۱,۳,۵-triazine analogs were identified as new PI۳K/mTOR inhibitors against osteosarcoma.