Design, Synthesis, and Pharmacological Evaluation of Triazine-based PI3K/mTOR Inhibitors for the Potential Treatment of Non-Small Cell Lung Cancer

Abstract

Dysregulated activation of the PI3K/AKT/mTOR pathway is crucial in the development of cancer, and disrupting it could potentially lead to cancer suppression, making it a viable strategy for cancer treatment. Here, as a consecutive work of our team, we described the identification and optimization of PI3K/mTOR inhibitors based on triazine scaffold, which exhibited potent PI3K/mTOR inhibitor activity. The systematically structure-activity relationship (SAR) results demonstrated that compound 5nh displayed high efficacy against PI3Kα and mTOR, with the IC₅₀ values of 0.45 nM and 2.9 nM, respectively. Importantly, compared to the lead compound PKI-587, 5nh demonstrated significant inhibitory activity against non-small-cell lung cancer (NSCLC) cell lines, particularly HCC-827, with a 43-fold increase (3.5 nM vs 150 nM). Additionally, the compound showed effective inhibition against the EGFR-resistant variant HCC-827(GR) cell line. Mechanism validation demonstrated that 5nh significantly interfered with the PI3K/AKT/mTOR signaling pathway in HCC-827 cells. Furthermore, the oral pharmacokinetic properties of 5nh had been observably improved, with AUC_0-t and C_max increasing by 13-16 times at a dose of 10 mg/kg in mice. Importantly, the in vivo efficacy study demonstrated that orally treatment of 5nh led to significant tumor growth suppression, with a TGI value of 84.4%. Collectively, our systematically medicinal chemistry campaigns suggested that 5nh, a novel oral available triazine derivative, held promise as a candidate for therapy of NSCLC by targeting the PI3K/AKT/mTOR cascade.