Synthesis and Biological Evaluation of a 5-6-5 Imidazole-Phenyl-Thiazole Based α-Helix Mimetic

The development of small molecules that disrupt protein−protein interactions is a key goal in addressing a number of disease states. The α-helix is commonly found at protein interaction interfaces and has been the focus of substantial small molecule mimetic efforts. One of the primary drawbacks of many small molecule α-helix mimetics is their hydrophobic core structures. To address this problem we have developed a novel scaffold based on a more water soluble 5-6-5 imidazole-phenyl-thiazole core. An inhibitor of this class has been shown to disrupt the Cdc42/Dbs protein−protein interaction at micromolar concentrations and may be useful in overcoming Cdc42-induced tumor resistance to anticancer therapies.