Discovery and characterization of small molecule Rac1 inhibitors
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Jamie L. Arnst1,2, Ashley L. Hein1, Margaret A. Taylor2, Nick Y. Palermo3, Jacob I. Contreras2, Yogesh A. Sonawane2, Andrew O. Wahl1, Michel M. Ouellette4,5, Amarnath Natarajan2,6,7, Ying Yan1,5
1Department of Radiation Oncology, University of Nebraska Medical Center Omaha, Nebraska, United States of America
2Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center Omaha, Nebraska, United States of America
3Holland Computing Center University of Nebraska-Lincoln Omaha, Nebraska, United States of America
4Department of Internal Medicine, University of Nebraska Medical Center Omaha, Nebraska, United States of America
5Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center Omaha, Nebraska, United States of America
6Department of Pharmaceutical Sciences, University of Nebraska Medical Center Omaha, Nebraska, United States of America
7Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center Omaha, Nebraska, United States of America
Amarnath Natarajan, email: email@example.com
Ying Yan, email: firstname.lastname@example.org
Keywords: GTPase, Ras-related C3 botulinum toxin substrate 1 (Rac1), Cdc42, Ras homolog gene family member A (RhoA), inhibitor
Received: August 20, 2016 Accepted: March 16, 2017 Published: March 29, 2017
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.
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