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

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Abstract

The development of small molecules that disrupt protein-protein interactions is a key goal in addressing a number of disease states. The alpha-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 alpha-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.

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