Background: ABCG2 plays a critical role in multi-drug resistance in a variety of cancers. Its activity is influenced by ATP hydrolysis and substrate transport, which are synergistic processes but in two independent sites. However, there was no QSAR study of the ABCG2 inhibitors for the two binding sites respectively. Methods: in current study, a QSAR model of ATP binding site was built using DCG scoring strategy, it was used to optimize the structure of a tyrosine kinase inhibitor to avoid the potential drug resistance. Results: a series of novel dual target compounds with arylamide skeleton were obtained, which showed notable activity in enzyme activity test. Compound 7c and 7i showed significant inhibitory activity against drug-resistant cells. Conclusions: the QSAR of ATP binding site of ABCG2 was first discussed, the dual-target compound 7c proposed a new strategy to reverse drug resistance.