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.

Small-Molecule Protein-Protein Interaction Inhibitor of Oncogenic Rho Signaling / Diviani, Dario; Raimondi, Francesco; Del Vescovo, Cosmo D.; Dreyer, Elisa; Reggi, Erica; Osman, Halima; Ruggieri, Lucia; Gonano, Cynthia; Cavin, Sabrina; Box, Clare L.; Lenoir, Marc; Overduin, Michael; Bellucci, Luca; Seeber, Michele; Fanelli, Francesca. - In: CELL CHEMICAL BIOLOGY. - ISSN 2451-9456. - ELETTRONICO. - 23:9(2016), pp. 1135-1146.

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