A series of flavone analogues were synthesized and evaluated for their antiproliferation activity against breast cancer cells. The IC(50) of compound 10 and 24 were determined to be at 5 μM. These compounds were used as baits to screen breast cancer cDNA expression phage display proteome library. DNA sequencing of the binding phages suggests that eEF1A1 is a target protein for 10 and 24. Further optimization of these compounds led to the discovery of 39 with higher cytotoxic potency (IC(50) = 1 μM) and binding to eEF1A2. Biological and biochemical data suggest that eEF1A2 might be a therapeutic target and that 39 is an excellent lead compound for further development.