Design, synthesis, and pharmacological evaluation of triazine-based PI3K/mTOR inhibitors for the potential treatment of non-small cell lung cancer.

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 IC 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 and C 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.