1. Small-Molecule Protein-Protein Interaction Inhibitor of Oncogenic Rho Signaling
- Author
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Cynthia Gonano, Erica Reggi, Francesco Raimondi, Michael Overduin, Francesca Fanelli, Clare L. Box, Elisa Dreyer, Dario Diviani, Halima Osman, Lucia Ruggieri, Michele Seeber, Sabrina Cavin, Luca Bellucci, Cosmo D. del Vescovo, Marc Lenoir, Diviani, D., Raimondi, F., Del Vescovo, C. D., Dreyer, E., Reggi, E., Osman, H., Ruggieri, L., Gonano, C., Cavin, S., Box, C. L., Lenoir, M., Overduin, M., Bellucci, L., Seeber, M., and Fanelli, F.
- Subjects
0301 basic medicine ,Models, Molecular ,rho GTP-Binding Proteins ,RHOA ,Clinical Biochemistry ,A Kinase Anchor Proteins ,RhoGEF ,Biochemistry ,Protein–protein interaction ,Minor Histocompatibility Antigens ,Small Molecule Libraries ,comparative modeling ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Proto-Oncogene Proteins ,AKAP13 oncogene ,Drug Discovery ,Humans ,Molecular Biology ,Pharmacology ,Virtual screening ,biology ,Molecular Structure ,Drug Discovery3003 Pharmaceutical Science ,Mutagenesis ,Ras GTPases ,Alanine scanning ,virtual screening ,Molecular medicine ,Small molecule ,Phenotype ,3. Good health ,Cell biology ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,Ras GTPase ,RhoGEFs ,Protein Binding ,Signal Transduction - Abstract
Uncontrolled activation of Rho signaling by RhoGEFs, in particular AKAP13 (Lbc) and its close homologs, isimplicated in a number of human tumors with poor prognosis and resistance to therapy. Structure predictions and alanine scanning mutagenesis of Lbc identified a circumscribed hot region for RhoA recognition and activation. Virtual screening targeting that region led to the discovery of an inhibitor of Lbc-RhoA interaction inside cells. By interacting with the DH domain, the compound inhibits the catalytic activity of Lbc, halts cellular responses to activation of oncogenic Lbc pathways, and reverses a number of prostate cancer cell phenotypes such asproliferation, migration, and invasiveness. This study provides insights into the structural determinants of Lbc-RhoA recognition. This is a successful example of structure-based discovery of a small protein-protein interaction inhibitor able to halt oncogenic Rho signaling incancer cells with therapeutic implications.
- Published
- 2014