Design, Synthesis, and Biological Evaluation of Imidazopyrazinone Derivatives as Antagonists of Inhibitor of Apoptosis Proteins (IAPs)

Apoptosis inhibitor (IAP) proteins are overexpressed in many cancers and implicated in tumor growth, so the development of antagonist that disrupts with the binding of IAP to their partner protein is a promising therapeutic strategy. In an effort to increase cellular activity and improve favorable drug‐like properties, we newly designed and synthesized monovalent analogues based on imidazopyrazinone structure of 9. Optimization of cellular potency led to the identification of 17, which showed increase of submicromolar activity (GI50 = 234 nM) and caspase‐3 activation (6.3‐fold) in MDA‐MB‐231 breast cancer cells. These findings clearly show the potential for 17 as a promising monovalent antagonist for the development of an effective anticancer treatment. In order to improve cellular activity, we designed a new derivative 9 with the insertion of the carbonyl groups in LBW242 to reduce flexibility and to introduce a new R‐group.