Binding Site Broadens Prospects For Prostate-Cancer Drugs

In work that could aid the search for prostate cancer treatments, scientists have identified a new binding site in a cell-surface receptor that has become an important target for prostate cancer drugs. Last year, David A. Spiegel of Yale University and coworkers developed a class of small molecules called ARM-Ps (antibody-recruiting molecules targeting prostate cancer) that kill prostate cancer cells by a novel mechanism: They bind to cytotoxic antibodies and deliver them to prostate-specific membrane antigen (PSMA), a receptor on prostate cancer cell surfaces. Now, in a study of ARM-P analogs, Spiegel’s group has found a previously unreported arene-binding site in PSMA that improves binding affinities (J. Am. Chem. Soc., DOI: 10.1021/ja104591m). ARM-P derivatives that hit the new site have affinities as low as 20 pM, among the best reported affinities for PSMA. In addition to the site’s therapeutic implications, Spiegel says he believes its structural simplicity—it is composed of only three amino acids—“suggests the intriguing possibility that such sites are broadly present in the proteome and could serve as useful tools in the optimization of protein-ligand interactions in general.