Structure activity study of carbonic anhydrase IX: Selective inhibition with ureido-substituted benzenesulfonamides.

ABSTRACT: Ureido-substituted benzenesulfonamides (USBs) show great promise as selective and potent inhibitors for human carbonic anhydrase hCA IX and XII, with one such compound (SLC-0111/U-F) currently in clinical trials (clinical trials.gov, NCT02215850). In this study, the crystal structures of both hCA II (off-target) and an hCA IX-mimic (target) in complex with selected USBs (U-CH₃, U-F, and U-NO₂), at resolutions of 1.9 Å or better, are presented, and demonstrate differences in the binding modes within the two isoforms. The presence of residue Phe 131 in hCA II causes steric hindrance (U-CH₃, 1765 nM; U-F, 960 nM; U-NO₂, 15 nM) whereas in hCA IX (U-CH₃, 7 nM; U-F, 45 nM; U-NO₂, 1 nM) and hCA XII (U-CH₃, 6 nM; U-F, 4 n

SUBMITTER: Mboge MY 

PROVIDER: S-EPMC5946058 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature