FRAX597, a small-molecule pyridopyrimidinone, is a potent and ATP competitive inhibitor of the group I PAKs (PAK1 IC50= 8 nM, PAK2 IC50= 13 nM, PAK3 IC50= 19 nM).
The family of serine/threonine p21-activating kinases, known as PAK proteins, are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling, and they serve as targets for the small GTP binding proteins Cdc42 and Rac. PAK proteins involve in intracellular signaling pathways downstream of integrins and receptor-type kinases. This family of proteins play an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes.
FRAX597 is a group Ⅰ PAK inhibitor. Based on enzymatic assays, the inhibitory IC50 values of FRAX597 against group Ⅰ PAK members PAK1, PAK2 and PAK3 are 7.7 nM, 12.8 nM and 19.3 nM, respectively[3].When Nf2-null SC4 Schwann cells were treated with 1 μM FRAX597 for a period of 96h, it was shown that FRAX597 dramatically impaired cell proliferation from the 48h time point[3]. In a cell cycle analysis, results show that FRAX597 blocked the cell cycle in G1 phase. However, the absence of a sub-G1 population suggested that FRAX597 did not impact cell viability.In an orthotopic model of schwannomas established by injection of luciferase-tagged schwannoma cells into a myelinated nerve, oral administration of FRAX597 at the dose of 100 mg/kg once daily, starting from 10 days post tumor cell implantation and lasting for a period of 14 days, significantly slowed down tumor growth rate. FRAX597-treated cohort showed significantly lower average tumor weight compared with control at the end point of the experiment[3].
作用机制
Structural assay revealed that FRAX597 inhibited PAK1 kinase by occupying the ATP binding site. In details, a phenyl ring that traverses the gatekeeper residue and positions the thiazole in the back cavity of the ATP binding site, a site rarely targeted by kinase inhibitors, was characterized in the FRAX597/PAK1 complex[3].
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