An ureido-substituted benzenesulfonamide carbonic anhydrase inhibitor exerts a potent antitumor effect in vitro and in vivo.

Carbonic anhydrase IX (CA IX) is a tumor-specific metallo-enzyme upregulated during hypoxic conditions and implicated in several pathophysiological processes where tissue pH regulation is required such as cancer, cell invasion, metastatic and stem-like features, drug resistance and recurrence. Indeed, CA IX expression has been correlated with poor prognosis, aggressiveness and disease progression in several solid tumors, and its targeting has been proposed as a therapeutic approach to treat aggressive cancers. To date, several CA IX targeting approaches have been developed to inhibit its activity in neoplastic tissues including the clinical grade (Phase Ib/II) ureido-substituted benzenesulfonamide SLC-0111, which has been widely investigated over the past years. In this study, we carried out a detailed characterization of a SLC-0111 derivative, FC-531, evaluating its anti-tumor potential in parallel with SLC-0111 on a panel of human cell lines representative of different cancer types. Finally, we evaluated the safety profile of FC-531 in vivo and demonstrated its capacity to reduce tumor growth and metastatization in vivo. Together, our data provide the rationale for the exploitation of FC-531 as a potent CA IX inhibitor for the management of different CA IX- expressing solid tumors.