Small-Molecule Protein-Protein Interaction Inhibitor of Oncogenic Rho Signaling.

Détails

ID Serval
serval:BIB_7D29A4D26F55
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Small-Molecule Protein-Protein Interaction Inhibitor of Oncogenic Rho Signaling.
Périodique
Cell Chemical Biology
Auteur(s)
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., Fanelli F.
ISSN
2451-9456 (Electronic)
Statut éditorial
Publié
Date de publication
2016
Peer-reviewed
Oui
Volume
23
Numéro
9
Pages
1135-1146
Langue
anglais
Résumé
Uncontrolled activation of Rho signaling by RhoGEFs, in particular AKAP13 (Lbc) and its close homologs, is implicated 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 as proliferation, 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 in cancer cells with therapeutic implications.

Mots-clé
A Kinase Anchor Proteins/antagonists & inhibitors, A Kinase Anchor Proteins/metabolism, Humans, Minor Histocompatibility Antigens/metabolism, Models, Molecular, Molecular Structure, Neoplasms/drug therapy, Neoplasms/metabolism, Protein Binding/drug effects, Proto-Oncogene Proteins/antagonists & inhibitors, Proto-Oncogene Proteins/metabolism, Signal Transduction/drug effects, Small Molecule Libraries/chemistry, Small Molecule Libraries/pharmacology, rho GTP-Binding Proteins/antagonists & inhibitors, rho GTP-Binding Proteins/metabolism, AKAP13 oncogene, Ras GTPases, RhoGEFs, comparative modeling, virtual screening
Pubmed
Web of science
Création de la notice
14/09/2016 8:33
Dernière modification de la notice
20/08/2019 14:38
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