G-5555

G-5555 is a potent p21-activated kinase 1 (PAK1) inhibitor with K_is of 3.7 nM and 11 nM for PAK1 and PAK2, respectively. IC50 & Target: IC50: 11 nM (PAK2)^[1]
Ki: 3.7 nM (PAK1)^[1][2], 11 nM (PAK2)^[2] In Vitro: G-5555 is a potent PAK1 inhibitor with a K_i of 3.7 nM. G-5555 shows excellent kinase selectivity and inhibits only eight out of the 235 kinases tested other than PAK1 with inhibition >70%: PAK2, PAK3, KHS1, Lck, MST3, MST4, SIK2, and YSK1. The IC₅₀s of G-5555 against SIK2, PAK2, KHS1, MST4, YSK1, MST3 and Lck are 9, 11, 10, 20, 34, 43, 52 nM, respectively. In general, G-5555 demonstrates high selectivity for the group I PAKs. There is negligible activity for G-5555 against the hERG channel with IC₅₀ more than 10 μM in a patch clamp assay^[1]. G-5555 potently inhibits PAK2, with a K_i of 11 nM. In an array of 23 breast cancer cell lines, G-5555 has significantly greater growth inhibitory activity in cell lines that are PAK-amplified compared to non-amplified lines^[2]. In Vivo: G-5555 exhibits low blood clearance and an acceptable half-life. Good oral exposure (AUC = 30 μM•h) and high oral bioavailability (F = 80%) are achieved^[1]. In an H292 non-small cell lunger cancer (NSCLC) xenograft study in mice, G-5555 inhibits phosphorylation of the PAK1/2 downstream substrate mitogen-activated protein kinase 1 (MEK1) S298 and, when administered at an oral dose of 25 mg/kg b.i.d., imparts 60% tumor growth inhibition in this model13 and a PAK1 amplified breast cancer xenograft model, MDAMB-175^[2].