[CAS NO. 898044-15-0] PF-3758309
PRODUCTS SPECIFICATIONS [898044-15-0]
DESCRIPTION [898044-15-0]
Overview
| MDL | MFCD18633226 |
|---|---|
| Molecular Weight | 490.62 |
| Molecular Formula | C25H30N8OS |
| SMILES | CC1=NC2=C(SC=C2)C(NC3=NNC4=C3CN(C(N[C@@H](C5=CC=CC=C5)CN(C)C)=O)C4(C)C)=N1 |
5 Publications Citing Use of MCE
Summary
PF-3758309 (PF-03758309) is a potent, orally available, and reversible ATP-competitive inhibitor of PAK4 ( K d = 2.7 nM; K i =18.7 nM). PF-3758309 has the expected cellular functions of a PAK4 inhibitor: inhibition of anchorage-independent growth, induction of apoptosis , cytoskeletal remodeling, and inhibition of proliferation [1] [2] [3] .
IC50 & Target
|
PAK4 18.7 nM (Ki) |
PAK1 13.7 nM (Ki) |
PAK5 18.1 nM (Ki) |
PAK6 17.1 nM (Ki) |
PAK2 190 nM (IC 50 ) |
PAK3 99 nM (IC 50 ) |
PAK4 2.7 nM (Kd) |
In Vitro
PF-3758309 has similar enzymatic potency against the kinase domains of the other group B PAKs (PAK5, K
i
=18.1 nM; PAK6, K
i
=17.1 nM) and group A PAK1 (K
i
=13.7 nM), but is less active against the other two group A PAKs (PAK2, IC
50
=190 nM; PAK3, IC
50
=99 nM)
[1]
.
In cells, PF-3758309 inhibits phosphorylation of the PAK4 substrate GEF-H1 (IC
50
=1.3 nM) and anchorage-independent growth of a panel of tumor cell lines (IC
50
=4.7 nM)
[1]
.
PF-3758309 also inhibits endogenous pGEF-H1 accumulation in HCT116 cells. PF-3758309 potently inhibits cellular proliferation (IC
50
=20 nM) and anchorage-independent growth (IC
50
=27 nM) of A549 cells
[1]
.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
PF-3758309 (7.5-30 mg/kg; p.o.; twice daily for 9-18 days) results in statistically significant tumor growth inhibition (TGI) in HCT116 and A549 models [1] .
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
| Animal Model: | Female nu/nu, CRL breed 6–8 weeks old mice (bearing HCT116 and A549 tumors) [1] |
| Dosage: | 7.5-30 mg/kg |
| Administration: | Oral administration; twice daily for 9-18 days |
| Result: | Significant tumor growth inhibition (TGI) in HCT116 and A549 models. |
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date | Phase |
|---|---|---|---|---|
| NCT00932126 | Pfizer |
Advanced Solid Tumors
|
September 2009 | Phase 1 |
Appearance
Solid
Shipping
Room temperature in continental US; may vary elsewhere.
Storage
| Powder | -20°C | 3 years |
|---|---|---|
| 4°C | 2 years | |
| In solvent | -80°C | 6 months |
| -20°C | 1 month |
Solvent & Solubility
DMSO : ≥ 100 mg/mL ( 203.82 mM )
* "≥" means soluble, but saturation unknown.
Stock Solutions
| Concentration Solvent Mass | 1 mg | 5 mg | 10 mg |
|---|
| 1 mM | 2.0382 mL | 10.1912 mL | 20.3824 mL |
| 5 mM | 0.4076 mL | 2.0382 mL | 4.0765 mL |
| 10 mM | 0.2038 mL | 1.0191 mL | 2.0382 mL |
References
- [1] Murray, Brion W., et al. Small-molecule p21-activated kinase inhibitor PF3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proceedings of the National Academy of Sciences of the United States of America (2010), 107(20), 9446-9451, S94
- [2] Zhao ZS, et al. Do PAKs make good drug targets? F1000 Biol Rep. 2010 Sep 23;2:70.
- [3] Ryu BJ, et al. PF-3758309, p21-activated kinase 4 inhibitor, suppresses migration and invasion of A549 human lung cancer cells via regulation of CREB, NF-κB, and β-catenin signalings. Mol Cell Biochem. 2014 Apr;389(1-2):69-77.
- [4] Pitts TM, et al. Association of the epithelial-to-mesenchymal transition phenotype with responsiveness to the p21-activated kinase inhibitor, PF-3758309, in colon cancer models. Front Pharmacol. 2013 Mar 28;4:35.