Description
PF-03758309 is a potent, ATP-competitive, pyrrolopyrazole inhibitor of PAK4 with IC50 of 1.3 nM.
Product Overview
PF-3758309 is an inhbitor of PAK4 with IC50 of 1.3 nM. P21-activated kinases (PAKs) are the family of serine/theronine kinases, which play important role in linking Rho GTPase to cytoskeleton reorganization and nuclear signaling. PAK4 is a member of PAKs family, specifically responsive for interacting with GTP bound form of Cdc42 and JNK family. PAK4 is involved in filopodia formation and may play a role in the reorganization of the actin cytoskeleton. Biochemical study had identified that PF-3758309 was an ATP-competitive inhibitor of PAK4, which inhibited the kinase activity. When PAK4 was screened with a panel of tumor cell lines, it was found PF-3758309 inhibited the phosphorylation of PAK4 substrate GEF-H1, and also the PAK4-induced anchorage-independent cell growth, with IC50 value of 1.3 nM and 4.7 ±3 nM respectively. When PF-3758309 was screened with a panel of PAKs related kinases, it exhibited good potency and specificity for PAK4.Cell analysis confirmed that PF-3758309 modulates PAK4-dependent signaling nodes and identifies unexpected links to additional p53pathways. In vivo activity of PF-3758309 was examined in a panel of human xenograft model, including HCT116 and A549 model. Twice daily oral administration of PF-3758309 (7.5-30 mg/kg BID) for 9-18 days resulted in significant inhibition of tumor growth in all the models. The tumor growth was shown to be caused by PAK-dependent pathways in HCT116 and A549 model. Additionally, PF-3758309 was shown to regulate PAK-associated cell proliferation and survival in certain models. Therefore, PF-3758309 exhibited inhibitory activity on PAK4.
Synonyms
PF 3758309; PF3758309
IC50
Ki=18.7 nM, Kd = 2.7 nM
Molecular Formula
C25H30N8OS
Chemical Name
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide
Solubility
Soluble in DMSO > 10 mM
Shipping Conditions
Evaluation sample solution: ship with blue ice. All other available size: ship with RT, or blue ice upon request
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