The further structural optimizations were focused on the introducing different cinnamon acyl moieties, leading to the discovery of iV26-9-10 bearing an indole ring (Supplementary Fig. 1e), which showed the best activity in inducing NOXA accumulation in both H358 and H2170 lung cancer cells with partial inactivation of cullin-5 neddylation (Supplementary Fig. 1f). The gene discussed is CUL5; the disease is lung carcinoma.