Background: Suppression of cancer metastasis is an urgent therapeutic need because metastasis is a major cause of high mortality in different types of cancers including lung cancer. Overexpression of a disintegrin and metalloprotease 9 (ADAM9), a member of the ADAM family of type I transmembrane proteins, is observed in many cancers and correlates with lung cancer brain metastasis. Since it contributes to tumorigenesis due to its ability in cleaving and releasing a number of molecules that involves cancer progression, it would be a potential target for lung cancer treatment. Methods: We have performed the genome-wide approach to explore ADAM9-regulated genes. Moreover, we have developed small compounds as ADAM9 inhibitors to target ADAM9’s catalytic domain using virtual screening and evaluated them by inhibiting ADAM9-mediated downstream pathways. Results: Overexpression of ADAM9 in lung cancer cells promotes tumor metastasis. Several ADAM9-mediated pathways are investigated from RNA-seq analysis. In the other hand, we have validated the potency of developed small compounds in reducing ADAM9 protease activity, cancer cell growth, and cell migration. In tumor animal models, ADAM9 inhibitors exhibited high efficacy to reduce cancer progression in animals bearing lung tumors. Notably, no liver and kidney toxicity were detected, suggesting no severe toxicity after drug treatment. Conclusions: We demonstrate inhibition of ADAM9 activity by potential ADAM9 inhibitor provide anti-lung tumor benefits in vitro and in vivo. Notably, ADAM9 inhibitor treatment has no systemically acute toxicity in mice. Thus, targeting ADAM9 provides a potential strategy for lung cancer treatment.
