Discovery and characterization of small molecule Rac1 inhibitors

Authors

Jamie L. Arnst, University of Nebraska Medical Center
Ashley L. Hein, University of Nebraska Medical Center
Margaret A. Taylor, University of Nebraska Medical Center
Nick Y. Palermo, University of Nebraska-LincolnFollow
Jacob I. Contreras, University of Nebraska Medical Center
Yogesh A. Sonawane, University of Nebraska Medical Center
Andrw O. Wahl, University of Nebraska Medical Center
Michel M. Ouellette, University of Nebraska Medical Center
Amarnath Natarajan, University of Nebraska Medical CenterFollow
Ying Yan, University of Nebraska Medical CenterFollow

Date of this Version

2017

Citation

Oncotarget, 2017, Vol. 8, (No. 21), pp: 34586-34600.

Comments

Copyright: Arnst et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License.

Abstract

Aberrant activation of Rho GTPase Rac1 has been observed in various tumor types, including pancreatic cancer. Rac1 activates multiple signaling pathways that lead to uncontrolled proliferation, invasion and metastasis. Thus, inhibition of Rac1 activity is a viable therapeutic strategy for proliferative disorders such as cancer. Here we identified small molecule inhibitors that target the nucleotide-binding site of Rac1 through in silico screening. Follow up in vitro studies demonstrated that two compounds blocked active Rac1 from binding to its effector PAK1. Fluorescence polarization studies indicate that these compounds target the nucleotide-binding site of Rac1. In cells, both compounds blocked Rac1 binding to its effector PAK1 following EGF-induced Rac1 activation in a dose-dependent manner, while showing no inhibition of the closely related Cdc42 and RhoA activity. Furthermore, functional studies indicate that both compounds reduced cell proliferation and migration in a dose-dependent manner in multiple pancreatic cancer cell lines. Additionally, the two compounds suppressed the clonogenic survival of pancreatic cancer cells, while they had no effect on the survival of normal pancreatic ductal cells. These compounds do not share the core structure of the known Rac1 inhibitors and could serve as additional lead compounds to target pancreatic cancers with high Rac1 activity.