Synthetic inhibitors of proline-rich ligand-mediated protein-protein interaction: potent analogs of UCS15A.

The proline-rich motif in proteins is known to function as a ligand sequence that binds to protein modules such as SH3, WW, and several other protein interaction domains. These proline-rich ligand-mediated protein-protein interactions (abbreviated PLPI) are important in many signaling pathways that are involved in various diseases. Our previous studies showed that UCS15A, produced by Streptomyces species, inhibited PLPI. Here we report on synthetic analogs of UCS15A that show more potent activity than UCS15A in inhibiting PLPI. A synthetic analog, compound 2c, blocked in vitro PLPI of Sam68-Fyn-SH3 as well as in vivo PLPI of Grb2-Sam68 and Grb2-Sos1. Activation of MEK was also inhibited by compound 2c. Unlike UCS15A, compound 2c was an order of magnitude less cytotoxic and did not cause morphological changes in treated cells.