[1P-81] Discovery of helix mimetic inhibitors targeting the interactions between the transcriptional activators and coactivator
Protein-protein interactions (PPIs) are involved in various diseases such as cancers, and thus PPI inhibition is one of effective approaches to drug discovery. Since many PPIs are mediated by α-helices, helix mimetics is promising as PPI inhibitors. Here, we designed helix mimetic inhibitors of low-to-medium molecular weight compounds targeting the interactions of the KIX domain of the transcriptional coactivator CBP with the transcriptional activators c-Myb and MLL, which are intrinsically disordered but form α-helices upon binding to KIX. From the compound library mimicking single turns of α-helices, we selected 74 compounds by virtual screening and obtained 12 hit compounds that interact with KIX by thermal shift assay and surface plasmon resonance. We further screened 128 additional compounds resembling the hit compounds and found 43 additional hits. From them, we finally obtained a helix mimetic compound exhibiting a potent growth inhibitory activity in human promyelocytic leukemia cells. These results suggest that our strategy is useful for efficiently designing PPI inhibitors.