PF-3758309

Short Summary : PAK4 inhibitor

Category : Cell Cycle/Checkpoint|PAK4

Purity : 0.98

CAS Number : 898044-15-0

Formula : C25H30N8OS

Molecular Weight : 490.62

SMILE : CC1=NC2=C(C(=N1)NC3=NNC4=C3CN(C4(C)C)C(=O)NC(CN(C)C)C5=CC=CC=C5)SC=C2

Solubility : >24.5mg/mL in DMSO

Storage : Store at -20°C

Description : PF-3758309 is an inhbitor of PAK4 with IC50 of 1.3 nM [1].
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 [1]. 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 [1]. When PF-3758309 was screened with a panel of PAKs related kinases, it exhibited good potency and specificity for PAK4 [1]. Cell analysis con rmed that PF-3758309 modulates PAK4-dependent signaling nodes and identi es unexpected links to additional p53pathways [1].
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 [1].
Reference:[1] Murray B W et al. , Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proc Natl Acad Sci USA. 2010, 107(20): 9446-9451.

Download datasheet