Discovery and characterization of small molecule Rac1 inhibitors.

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.

• Authors: Jamie L Arnst, Ashley L Hein, Margaret A Taylor, Nick Y Palermo, Jacob I Contreras, Yogesh A Sonawane, Andrew O Wahl, Michel M Ouellette, Amarnath Natarajan, Ying Yan
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 21 Pg. 34586-34600 (May 23 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28410221 (Publication Type: Journal Article)

Chemical References

• RAC1 protein, human
• Small Molecule Libraries
• RHOA protein, human
• PAK1 protein, human
• p21-Activated Kinases
• cdc42 GTP-Binding Protein
• rac1 GTP-Binding Protein
• rhoA GTP-Binding Protein

Topics

• Binding Sites (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Screening Assays, Antitumor
• Humans
• Pancreatic Neoplasms (drug therapy, metabolism)
• Protein Binding (drug effects)
• Small Molecule Libraries (pharmacology)
• cdc42 GTP-Binding Protein (metabolism)
• p21-Activated Kinases (metabolism)
• rac1 GTP-Binding Protein (antagonists & inhibitors, chemistry)
• rhoA GTP-Binding Protein (metabolism)