product name PF-3758309
Description: PF-03758309 is a potent, ATP-competitive, pyrrolopyrazole inhibitor of PAK4 with IC50 of 1.3 NM. PF-3758309 is also an orally bioavailable small-molecule inhibitor of PAK4 with potential antineoplastic activity. PF-03758309 binds to PAK4 and inhibits PAK4 activity and cancer cell growth. PAK4, a serine/threonine kinase belonging to the p21-activated kinase (PAK) family, is often upregulated in a variety of cancer cell types and plays an important role in cancer cell motility, proliferation, and survival.
References: Proc Natl Acad Sci U S A. 2010 May 18;107(20):9446-51.
490.62
Formula
C25H30N8OS
CAS No.
898044-15-0
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 98 mg/mL (199.7 mM)
Water: <1 mg/mL
Ethanol: 98 mg/mL (199.7 mM)
Solubility (In vivo)
Synonyms
PF-03758309
other peoduct :
| In Vitro |
In vitro activity: PF-3758309 is a potent (Kd = 2.7 nM), ATP-competitive inhibitor of PAK4 with Ki of 18.7 nM. In cells, PF-3758309 inhibits phosphorylation of the PAK4 substrate GEF-H1 (IC50 = 1.3 nM) and anchorage-independent growth of a panel of tumor cell lines (IC50 = 4.7 nM). PF-3758309 also inhibits endogenous pGEF-H1 accumulation in HCT116 cells. PF-3758309 potently inhibits cellular proliferation (IC50 = 20 nM) and anchorage-independent growth (IC50 = 27 nM) of A549 cells. Kinase Assay: TR-293-KDG cells are constructed from HEK293 cells stably transfected with tetracycline-inducible PAK4-kinase domain (amino acids 291-591) and constitutively expressed HA-tagged GEFH1ΔDH (amino acids 210-921). TR-293-KDG cells are incubated for 3 h with PF-3758309, captured on an anti-HA antibody-coated plate, detected with an anti-phospho-S810-GEF-H1 antibody, and quantified with a horseradish peroxidase-goat anti-rabbit antibody conjugate. Cell Assay: A panel of cancer cell lines is used to test the potency of PF-3758309. On day 1, cells are plated on 384-well plates. Onday2, compounds are added to the cell culture. The cells are incubated with the compound for 3 days. On day 5, all media are aspirated from the wells. Dose-dependent effects of PF-3758309 on cell proliferation are quantified via the CellTiter-Glo Luminescent Cell Viability Assay(a,b,c), which is a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present, an indicator of metabolically active cells. Proliferation data displayed for HEK293T, HCT116, and SKOV3 cells are measured using the Cyquant NF assay as specified by the manufacturer. Briefly, 24 h after seeding on 384-well plates, cells are treated with vehicle or PF-3758309, Dasatinib, or the positive control, Bleomycin (60 mU/ mL).72 hours after drug treatment, cell proliferation is measured. Results for each drug are normalized to vehicle control and expressed as a percentage of maximum assay inhibition relative to Bleomycin. Error bars represent the SD from at least three experiments. |
|---|---|
| In Vivo | PF-3758309 blocks the growth of multiple human tumor xenografts, with a plasma EC50 value of 0.4 nM in the most sensitive model. PF-3758309 is antiproliferative and induces apoptosis in a HCT116 tumor model. |
| Animal model | Xenograft tumors in nude mice |
| Formulation & Dosage | Dissolved in 0.5% methylcellulose; 7.5-30 mg/kg BID; p.o. administration |
| References | Proc Natl Acad Sci U S A. 2010 May 18;107(20):9446-51. |
