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Characterization of EHop‐016, a novel small molecule inhibitor of Rac GTPase
Author(s) -
Humphries-Bickley Tessa Winifred,
Castillo-Pichardo Linette,
Montalvo-Ortiz Brenda L.,
Hernandez Eliud,
Vlaar Cornelis P.,
Dharmawardhane Suranganie
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb243
Subject(s) - rac gtp binding proteins , guanine nucleotide exchange factor , rac1 , cdc42 , lamellipodium , microbiology and biotechnology , pak1 , cancer cell , gtpase , cell migration , actin cytoskeleton , chemistry , biology , cancer research , cancer , cell , kinase , cytoskeleton , biochemistry , signal transduction , genetics
The Rho GTPase Rac regulates actin cytoskeleton reorganization to form cell surface extensions (lamellipodia) required for cell migration/invasion during cancer metastasis. Interference of the interaction of Rac with its direct upstream activators, guanine nucleotide exchange factors (GEFs) is a viable strategy for inhibiting cancer progression. We synthesized EHop‐016, a novel inhibitor of Rac activity, based on the structure of the established Rac/Rac‐GEF inhibitor NSC23766 . Herein, we demonstrate that EHop‐016 inhibits Rac activity in the MDA‐MB‐435 metastatic cancer cells that overexpress Rac and exhibit high endogenous Rac activity. The IC 50 of 1.1 μM for Rac inhibition by EHop‐016 is ~100‐fold lower than for NSC23766 . EHop‐016 is specific for Rac1 and Rac3 at concentrations ≤ 5 μM. At higher concentrations, EHop‐016 inhibits the close homolog Cdc42. In MDA‐MB‐435 cells, EHop‐016 (≤ 5 μM) inhibits the association of the Rac‐GEF Vav2 with a nucleotide‐free Rac1(G15A), which has a high affinity for activated GEFs. However, EHop‐016 does not affect the association of the Rac‐GEF Tiam‐1 with Rac1(G15A) at similar concentrations. EHop‐016 decreases Rac‐downstream effects of p21‐activated kinase (PAK)1 activity and directed migration of metastatic cancer cells. Therefore, EHop‐016 holds promise as a targeted therapeutic agent for the treatment of metastatic cancers with high Rac and Vav2 activity.