PF-3758309 is a potent, orally bioavailable, and reversible ATP-competitive inhibitor of PAK4 (Kd= 2.7 nM; Ki=18.7 nM). It exhibits typical cellular functions associated with PAK4 inhibition, including inhibition of anchorage-independent growth, induction of apoptosis, cytoskeletal remodeling, and inhibition of proliferation[1][2][3].
体内研究
PF-3758309 (7.5-30 mg/kg; pO.; twice daily for 9-18 days) induces statistically significant tumor growth inhibition (TGI) in HCT116 and A549 models[1].
体外研究
PF-3758309 exhibits comparable enzymatic potency against the kinase domains of other group B PAKs (PAK5, Ki=18.1 nM; PAK6, Ki=17.1 nM) and group A PAK1 (Ki=13.7 nM), but displays lower activity against the other two group A PAKs (PAK2, IC50=190 nM; PAK3, IC50=99 nM)[1].
PF-3758309, in cellular context, suppresses phosphorylation of the PAK4 substrate GEF-H1 (IC50=1.3 nM) and inhibits anchorage-independent growth across various tumor cell lines (IC50=4.7 nM)[1].
PF-3758309 additionally suppresses the accumulation of endogenous pGEF-H1 in HCT116 cells. It demonstrates potent inhibition of cellular proliferation (IC50=20 nM) and anchorage-independent growth (IC50=27 nM) in A549 cells[1].
PF-3758309 细胞研究
细胞系
浓度
检测类型
检测时间
活性说明
数据源
human MDA-MB-436 cells
Cytotoxic assay
24-48 h
Cytotoxicity against human MDA-MB-436 cells assessed as reduction in cell viability after 24 to 48 hrs by Celltiter-glo luminescence assay, IC50=0.79 nM
Cytotoxicity against human MDA-MB-436 cells assessed as reduction in cell viability after 24 to 48 hrs by Celltiter-glo luminescence assay, IC50=0.79 nM
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