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Small-Molecule Protein-Protein Interaction Inhibitor of Oncogenic Rho Signaling.
Cell Chemical Biology
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.
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
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