Identification of the first non-peptidic small molecule inhibitor of the c-Abl/14-3-3 protein–protein interactions able to drive sensitive and Imatinib-resistant leukemia cells to apoptosis

An in silico structure-based ligand design approach resulted in the identification of the first non-peptidic small molecule able to inhibit protein–protein interactions between 14-3-3 and c-Abl. This compound shows an anti-proliferative effect on human leukemia cells either sensitive or resistant to Imatinib, in consequence of the T315I mutation. It also mediates c-Abl release from 14-3-3 in a way similar to that found in response to Imatinib treatment.

Graphical abstractThe first non-peptidic small molecule able to bind 14-3-3 and to disrupt the c-Abl/14-3-3 complex was discovered by an in silico structure-based drug design approach. Its activity induces wild type and T315I Ba/F3 leukemia cells to apoptosis via cytoplasm-to-nucleus shuttling of c-Abl.Figure optionsDownload full-size imageDownload as PowerPoint slide