G-5555

G-5555 is an inhibitor of p21-activated kinase 1 (PAK1; K_i = 3.7 nM), a non-receptor serine/threonine kinase involved in tumorigenesis.¹ It is selective for PAK1 over the majority of targets in a panel of 235 kinases but does inhibit PAK2, PAK3, KHS1, LCK, MST3, MST4, SIK2, and YSK1 by greater than 70% with IC₅₀ values ranging from 9 to 52 nM. G-5555 inhibits phosphorylation of MEK, a downstream target of PAK1, in EBC1 cells (IC₅₀ = 69 nM). G-5555 (10, 20, and 30 mg/kg) dose-dependently reduces phosphorylation of MEK in tumors from an H292 non-small cell lung cancer (NSCLC) mouse xenograft model. G-5555 inhibits hERG channels less than 50% at a concentration of 10 μM, indicating the potential for a low risk of QT interval prolongation and potentially fatal arrhythmias.²

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1. Ndubaku, C.O., Crawford, J.J., Drobnick, J., et al. Design of selective PAK1 inhibitor G-5555: Improving properties by employing an unorthodox low-pKa polar moiety. ACS Med. Chem. Lett. 6(12), 1241-1246 (2015).

2. Braga, R.C., Alves, V.M., Silva, M.F., et al. Tuning HERG out: Antitarget QSAR models for drug development. Curr. Top. Med. Chem. 14(11), 1399-1415 (2014).