tcsc0773 PF-3758309

PF-3758309 is an inhbitor of PAK with IC₅₀ of 1.3 nM for PAK4.

IC50 & Target: IC50: 1.3 nM (PAK4)^[1]

In Vitro: F-3758309 binds directly to PAK4 with an in vitro potency of 2.7-4.5 nM. PF-3758309 has similar enzymatic potency against the kinase domains of the other group B PAKs (PAK5, K_i=18.1±5.1 nM; PAK6, K_i=17.1±5.3 nM) and group A PAK1 (K_i=13.7±1.8 nM), but is less active against the other two group A PAKs (PAK2, IC₅₀=190 nM; PAK3, IC₅₀=99 nM). PAK4 phosphorylates GEF-H1 on a previously characterized serine residue 810 and is inhibited by PF-3758309 (IC₅₀=1.3±0.5 nM). PF-3758309 also inhibits endogenous pGEF-H1 accumulation in HCT116 cells^[1]. PF-3758309 is profiled for its growth-inhibitory activity in a panel of 92 tumor cell lines, half of which exhibits IC₅₀ values of less than 10 nM^[2]. The proliferation of A549 cells is affected at the treatment with lower dosage (1 μM) of PF-3758309^[3].

In Vivo: PF-3758309 (7.5-30 mg/kg BID, p.o.) results in statistically significant tumor growth inhibition (TGI) in five models including HCT116 and A549 models. PF-3758309 (15 mg/kg BID, p.o.) is found to inhibit [³H]FLT uptake 32.5% in the HCT116 tumor xenografts by day 6. PF-3758309 treatment shows a significant increase in the apoptotic marker activated caspase 3 in HCT116 tumors^[1]. PF-3758309 (25 mg/kg, p.o.) exhibits antiproliferative effects on cell line xenografts^[4].