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.
Corradi
Valentina
V
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Siena, Italy.
Mancini
Manuela
M
Manetti
Fabrizio
F
Petta
Sara
S
Santucci
Maria Alessandra
MA
Botta
Maurizio
M
D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008958:Models, Molecular; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D054852:Small Molecule Libraries; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl