The Rac inhibitor EHop-016 was developed as a compound with the potential to inhibit
cancer metastasis. Inhibition of the first step of
metastasis, migration, is an important strategy for
metastasis prevention. The
small GTPase Rac acts as a pivotal binary switch that is turned "on" by
guanine nucleotide exchange factors (GEFs) via a myriad of
cell surface receptors, to regulate
cancer cell migration, survival, and proliferation. Unlike the related
GTPase Ras, Racs are not usually mutated, but overexpressed or overactivated in
cancer. Therefore, a rational Rac inhibitor should block the activation of Rac by its upstream effectors, GEFs, and the Rac inhibitor
NSC23766 was developed using this rationale. However, this compound is ineffective at inhibiting the elevated Rac activity of metastatic
breast cancer cells. Therefore, a panel of small molecule compounds were derived from
NSC23766 and screened for Rac activity inhibition in metastatic
cancer cells. EHop-016 was identified as a compound that blocks the interaction of Rac with the GEF Vav in metastatic human
breast cancer cells with an IC50 of ~1μM. At higher concentrations (10μM), EHop-016 inhibits the related
Rho GTPase Cdc42, but not Rho, and also reduces cell viability. Moreover, EHop-016 inhibits the activation of the Rac downstream effector
p21-activated kinase, extension of motile actin-based structures, and cell migration. Future goals are to develop EHop-016 as a therapeutic to inhibit
cancer metastasis, either individually or in combination with current anticancer compounds. The next generation of EHop-016-based Rac inhibitors is also being developed.