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Small\u2010molecule inhibitors of 14\u20103\u20103 protein\u2013protein interactions (PPIs) are in high demand, both as tools to increase our understanding of 14\u20103\u20103 actions in human diseases and as leads to develop innovative therapeutic agents. Herein we present the discovery of novel 14\u20103\u20103 PPI inhibitors through a multidisciplinary strategy combining molecular modeling, organic synthesis, image\u2010based high\u2010content analysis of reporter cells, and in vitro assays using cancer cells. Notably, the two most active compounds promoted the translocation of c\u2010Abl and FOXO pro\u2010apoptotic factors into the nucleus and sensitized multidrug\u2010resistant cancer cells to apoptotic inducers such as doxorubicin and the pan\u2010Akt inhibitor GSK690693, thus becoming valuable lead candidates for further optimization. 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