Uses
EHT 1864 is an inhibitor of the Rac subfamily of Rho GTPases, that binds to Rac1, Rac1b, Rac2, and Rac3 with Kd values of 40, 50, 50, and 250 nM, respectively. It can reverse transformation of NIH 3T3 fibroblasts caused by constitutively activated Rac1, as well as Rac-dependent transformation caused by Tiam1 or Ras. EHT 1864 inhibits APP processing by γ-secretase, reducing Αβ40 and Αβ42 accumulation. It blocks breast cancer cell invasion in a collagen matrix assay and, at 10 μM, increases the size but decreases the density of dendritic spines of hippocampal neurons in culture.
Biological Activity
Inhibitor of Rac family GTPases. Blocks activation by direct binding to Rac1, Rac1b, Rac2 and Rac3 (K D values are 40, 50, 60 and 250 nM respectively). Inhibits Rac, Ras and Tiam-induced growth transformation of NIH-3T3 fibroblasts. Reduces β -amyloid peptide production in vivo .
Biochem/physiol Actions
EHT 1864 inhibits Rac function. It prevents Aβ40 and Aβ42 production in vitro without direct inhibition of g-secretase.
in vivo
EHT 1864 (oral administration) displays good tolerability, brain penetrance, and no genotoxicity. EHT 1864 (10 and 40 mg/kg/day; daily; 15 days; intraperitoneal injections) lowers brain Aβ 40 by 37% in guinea pigs[1].
References
[1] shutes a, onesto c, picard v, et al. specificity and mechanism of action of eht 1864, a novel small molecule inhibitor of rac family small gtpases. journal of biological chemistry, 2007, 282(49): 35666-35678.
