Discovery of novel hybrids of mTOR inhibitor and NO donor as potential anti-tumor therapeutics

Nitric oxide (NO) may be beneficial to overcoming drug resistance resulting from mutation of mTOR kinases and bypass mechanisms. In this study, a novel structural series of hybrids of mTOR inhibitor and NO donor were designed and synthesized via structure-based drug design (SBDD). Throughout the 20 target compounds, half of the compounds (13a, 13b, 19a-19d, 19f-19j) demonstrated attractive mTOR inhibitory activity with IC₅₀ at single-digit nanomolar level. In particular, 19f exerted superior anti-proliferative activity against HepG2, MCF-7, HL-60 cells (HepG2, IC₅₀ = 0.24 μM; MCF-7, IC₅₀ = 0.88 μM; HL-60, IC₅₀ = 0.02 μM) to that of the clinical investigated mTOR inhibitor MLN0128, and show mild cytotoxicity against normal cells with IC₅₀ over 10 μM. 19a, with the most potent mTOR inhibitory activity in this series (IC₅₀ = 3.31 nM), also displayed attractive cellular potency. In addition, 19f treatment in HL-60 reduces the levels of Phos-Akt and Phos-S6 in a dose-dependent manner, and releases NO in cells. In summary, 19f deserves further development as a novel mTOR-based multi-target anti-cancer agent.