Discovery of an Inhibitor of the Proteasome Subunit Rpn11.

The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have been validated in the treatment of multiple myeloma, with several FDA-approved therapeutics.

Investigating chelating sulfonamides and their use in metalloproteinase inhibitors.

Matrix metalloproteinase inhibitors (MMPi) utilize zinc-binding groups (ZBGs) to chelate the catalytic Zn(II) ion resulting in enzyme inhibition. Adapting findings from the literature of Zn(II) ion sensors, we previously reported chelating sulfonamide inhibitors of MMP-2, some of which showed excellent selectivity over other gelatinases (MMP-9). Herein, we greatly expand our investigation of chelating sulfonamides as MMP inhibitors (MMPi) with the synthesis and screening of several new libraries consisting of 2-phenyl-7-sulfonamidobenzimidazole, 2-phenyl-7-sulfonamidobenzoxazole, 7-sulfonamidobenzimidazole, 7-sulfonamidobenzoxazole, and 2-(2-sulfonamidophenyl)-quinoline ZBG derivatives.

Emerging trends in metalloprotein inhibition.

Numerous metalloproteins are important therapeutic targets that are gaining increased attention in the medicinal and bioinorganic chemistry communities. This Perspective article describes some emerging trends and recent findings in the area of metalloprotein inhibitor discovery and development. In particular, increasing recognition of the importance of the metal-ligand interactions in these systems calls for more input and consideration from the bioinorganic community to address questions traditionally confined to the medicinal chemistry community.