Development of erythrina-based PARP-1/FTase dual-target inhibitors against lung cancer epithelial-mesenchymal transition (EMT) in vivo and in vitro.

ABSTRACT

A novel series of erythrina derivatives as PARP-1/FTase inhibitors were synthesized, and evaluated for their biological activities. Compound T9 had excellent inhibitory effects on cell viability (A549 IC50 = 1.74 µM; A549/5-Fu IC50 = 1.03 µM) and in vitro enzyme activities (PARP-1 IC50 = 0.40 µM; FTase IC50 = 0.067 µM). Molecular docking and point mutation assays demonstrated the interaction of compound T9 with key amino acid residues. The compound T9 exhibited potent anti-proliferation and anti-migration capabilities against A549 and A549/5-Fu cells. PCR array and western blot results showed that compound T9 could effectively inhibit EMT-related proteins in A549 and A549/5-Fu cells, thereby inhibiting the development of lung cancer. Importantly, compound T9 could significantly inhibit tumor growth in the A549 xenograft tumor model (TGI = 65.3 %). In conclusion, this study was the first presentation of the concept of dual-target inhibitors of the PARP-1/FTase enzymes. It also provides the basis for further research and development of novel PARP-1/FTase inhibitors.