Biochem/physiol Actions

FRAX1036 is a potent, group I-selective p21-activated kinase (PAK) inhibitor (PAK1/4 Ki = 23 nM/1.4 µM; PAK1/4 IC50 = 2 nM/>500 nM; >96% PAK1/2/3 inhibition vs. 5.1%/8.2%/22.2% PAK4/5/6 inhibition at 1 µM) with significant inhibitory activity toward only 11 other kinases at a high concentration of 1 µM (78.7-100% inhibition) among a panel of 240. FRAX1036 exhibits higher antiproliferation activity in PAK negative regulator NF2-deficient meningioma cultures (NF2-/- Ben-Men-1/KT21-MG1 IC50 = 1.888/1.991 µM vs.NF2+/+ MN328/MN525 IC50 = 4.239/3.296 µM) by inhibiting cellular PAK autophosphorylation and downstream signaling events. When administered orally in a murine orthotopic meningioma model, FRAX1036 effectively suppresses the growth of established KT21 and Ben-Men tumors in vivo (30 mg/kg/d p.o.).