IQUIBICEN 23947
INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CIENCIAS EXACTAS Y NATURALES
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Dialkyl-guanidines as a novel series of Rac1 GTPase inhibitors: an interdisciplinary approach
Autor/es:
CIARLANTINI M; BARQUERO A; MARTÍN MIGUEL DODES TRAIAN; HERNÁN BUCCI; BAYO FINA JM; FIORE E; JAVIER RAMÍREZ; MARÍA JULIETA COMIN; DIANA WETZLER; DEFELIPE L; ADRIÁN TURJANSKI; MAZZOLINO RIZZO G
Lugar:
San Luis
Reunión:
Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Biofísica; 2019
Institución organizadora:
Sociedad Argentina de Biofísica
Resumen:
Rac1 is a GTPase which belongs to the Rho family of small GTP-binding proteins. Thesesmall GTPases regulate cytoskeletal and cell adhesion dynamics and thereby coordinatea wide range of cellular processes, including cell migration, cell polarity and cell cycleprogression. As aberrant activation of Rac1 is associated with cell malignanttransformation including tumorigenesis, angiogenesis, invasion, and metastasis, thisprotein is a promising target for drug development.As in all GTPases, Rac1 activity is controlled by the GDP/GTP exchange and the GTPhydrolysis. These slow reactions are catalyzed in cells by two kinds of regulatoryproteins. While the guanine exchange factors (GEFs) activate small GTPases catalyzingthe exchange of bound GDP for the cellular GTP, GTPase activating proteins (GAPs)accelerate the intrinsic rate of GTP hydrolysis, leading to their inactivation. Thus, aninteresting strategy is to inhibit Rac1 through its activation cycle, particularly by thedisruption of the interaction between Rac1 and one specific GEF partner.We conducted an interdisciplinary approach that comprised the rational design,synthesis, and evaluation of a new family of inhibitors. The work involved computationaldocking experiments, compounds synthesis, antiproliferative, apoptosis and cellmigration assays, in vitro biophysical experiments with recombinant proteins and in vivomice assays.Based on structure/function information of the complex between Rac1 and its GEF,Tiam1, and employing as starting point a previously reported inhibitor we developed anovel series of Rac1 GTPase inhibitors.# Part of this work corresponds to de Doctoral Thesis of MC
