Carboranes Enhance Enzyme Inhibitor

Replacing the terminal substituent group on a small-molecule drug candidate with a carborane cage significantly increases the molecule’s potency as an enzyme inhibitor, according to Mark W. Lee Jr. of the University of Missouri, Columbia, and coworkers (J. Med. Chem., DOI: 10.1021/jm300740t). Carboranes are symmetrical three-dimensional carbon-boron analogs of aromatic hydrocarbons. Their chemical stability, easy substitution, and ability to form strong hydrogen bonds with biomolecules have made them attractive pharmacophores in drug design. In a clinically promising example, Lee and coworkers tested the ability of carboranes to improve the activity of FK866, a pyridinylacrylamide compound with a terminal benzoyl­piperidine group. FK866 is specific for and strongly inhibits Nampt, an enzyme that facilitates recycling of nicotinamide and has recently been discovered to be a central link connecting cell metabolism, cancer, and inflammation. Lee’s team substituted similarly sized phenyl, adamantyl, and carboranyl groups for FK866’s benzoylpiperidine group. They found that carboranes outperformed all the other groups, with up to a 100-fold increase over FK866 in inhibiting Nampt in a commercial assay and up to 10-fold greater activity than FK866 against three human cancer cell lines.