Small-Molecule Protein-Protein Interaction Inhibitor of Oncogenic Rho Signaling.
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.
Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 27, 1005 Lausanne, Switzerland.
Dario
D
Diviani
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy.
Francesco
F
Raimondi
Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 27, 1005 Lausanne, Switzerland.
Cosmo D
CD
Del Vescovo
Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 27, 1005 Lausanne, Switzerland.
Elisa
E
Dreyer
Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 27, 1005 Lausanne, Switzerland.
Erica
E
Reggi
Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 27, 1005 Lausanne, Switzerland.
Halima
H
Osman
Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 27, 1005 Lausanne, Switzerland.
Lucia
L
Ruggieri
Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 27, 1005 Lausanne, Switzerland.
Cynthia
C
Gonano
Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 27, 1005 Lausanne, Switzerland.
Sabrina
S
Cavin
Institute of Cancer and Genomic Studies, University of Birmingham, Birmingham B15 2TT, UK.
Clare L
CL
Box
Institute of Cancer and Genomic Studies, University of Birmingham, Birmingham B15 2TT, UK.
Marc
M
Lenoir
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Michael
M
Overduin
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy.
Luca
L
Bellucci
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy.
Michele
M
Seeber
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy. Electronic address: fanelli@unimo.it.
Francesca
F
Fanelli
D054758:A Kinase Anchor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; D015778:Minor Histocompatibility Antigens; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; D020741:rho GTP-Binding Proteins
AKAP13 oncogene; Ras GTPases; RhoGEFs; comparative modeling; virtual screening