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

Dario Diviani,Francesco Raimondi,Cosmo D Del Vescovo,Elisa Dreyer,Erica Reggi,Halima Osman,Lucia Ruggieri,Cynthia Gonano,Sabrina Cavin,Clare L Box,Marc Lenoir,Michael Overduin,Luca Bellucci,Michele Seeber,Francesca Fanelli

doi:10.1016/j.chembiol.2016.07.015

Dario Diviani, Francesco Raimondi + Show 13 more

Open Access

https://doi.org/10.1016/j.chembiol.2016.07.015

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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.

Highlights

A main family of the Ras superfamily of small GTPases comprises Rho (Ras homolog) proteins (Jaffe and Hall, 2005; Colicelli, 2004)
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
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

Summary

Introduction

A main family of the Ras superfamily of small GTPases comprises Rho (Ras homolog) proteins (Jaffe and Hall, 2005; Colicelli, 2004). Rho GTPases and RhoGEFs play important roles in many aspects of cancer development and tumor progression (Karlsson et al, 2009; Cook et al, 2013; Wirtenberger et al, 2006; Feher et al, 2012). In this respect, the oncogenic function of the RhoGEF A-Kinase Anchoring Protein-Lbc (AKAP-Lbc [or AKAP13], hereinafter referred to as Lbc) was discovered a number of years ago (Toksoz and Williams, 1994). LARG, p115, and PRG are directly regulated by activated Ga12/13 proteins (i.e., only Ga12 in the case of Lbc) and are suggested to play a role in oncogenic transformations induced by G protein-coupled receptors (Diviani et al, 2001;Fukuhara et al, 1999, 2000; Hart et al, 1998; Aittaleb et al, 2009)

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