5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)34586-34600
Number of pages15
JournalOncotarget
Volume8
Issue number21
DOIs
StatePublished - Jan 1 2017

Fingerprint

Pancreatic Neoplasms
Nucleotides
Binding Sites
rho GTP-Binding Proteins
Fluorescence Polarization
Epidermal Growth Factor
Computer Simulation
Cell Movement
Neoplasms
Cell Proliferation
Neoplasm Metastasis
Cell Line
Therapeutics

Keywords

  • Cdc42
  • GTPase
  • Inhibitor
  • Ras homolog gene family member A (RhoA)
  • Ras-related C3 botulinum toxin substrate 1 (Rac1)

ASJC Scopus subject areas

  • Oncology

Cite this

Arnst, J. L., Hein, A. L., Taylor, M. A., Palermo, N. Y., Contreras, J. I., Sonawane, Y. A., ... Yan, Y. (2017). Discovery and characterization of small molecule Rac1 inhibitors. Oncotarget, 8(21), 34586-34600. https://doi.org/10.18632/oncotarget.16656

Discovery and characterization of small molecule Rac1 inhibitors. / Arnst, Jamie L.; Hein, Ashley L.; Taylor, Margaret A.; Palermo, Nick Y.; Contreras, Jacob I.; Sonawane, Yogesh A.; Wahl, Andrew O; Ouellette, Michel M; Natarajan, Amarnath; Yan, Ying.

In: Oncotarget, Vol. 8, No. 21, 01.01.2017, p. 34586-34600.

Research output: Contribution to journalArticle

Arnst, JL, Hein, AL, Taylor, MA, Palermo, NY, Contreras, JI, Sonawane, YA, Wahl, AO, Ouellette, MM, Natarajan, A & Yan, Y 2017, 'Discovery and characterization of small molecule Rac1 inhibitors', Oncotarget, vol. 8, no. 21, pp. 34586-34600. https://doi.org/10.18632/oncotarget.16656
Arnst JL, Hein AL, Taylor MA, Palermo NY, Contreras JI, Sonawane YA et al. Discovery and characterization of small molecule Rac1 inhibitors. Oncotarget. 2017 Jan 1;8(21):34586-34600. https://doi.org/10.18632/oncotarget.16656
Arnst, Jamie L. ; Hein, Ashley L. ; Taylor, Margaret A. ; Palermo, Nick Y. ; Contreras, Jacob I. ; Sonawane, Yogesh A. ; Wahl, Andrew O ; Ouellette, Michel M ; Natarajan, Amarnath ; Yan, Ying. / Discovery and characterization of small molecule Rac1 inhibitors. In: Oncotarget. 2017 ; Vol. 8, No. 21. pp. 34586-34600.
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