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Purity: ≥98%
PF-03758309 (PF03758309; PF-3758309; PF 03758309; PF3758309), a pyrrolopyrazole analog, is a novel, potent, orally bioavailable, and ATP-competitive small molecule inhibitor of PAK4 (p21-activated kinase 4) with potential antineoplastic activity. It inhibits PAK4 with an IC50 of 1.3 nM. As an inhibitor of PAK4, PF-3758309 has potential antineoplastic activity by binding to PAK4 and inhibiting 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.
| ln Vitro |
In comparison to the kinase domains of the other group B PAKs (PAK5, Ki=18.1 nM; PAK6, Ki=17.1 nM) and group A PAK1 (Ki=13.7 nM), PF-3758309 exhibits comparable enzymatic potency. However, it exhibits lower activity against the two other group A PAKs (PAK2, IC50=190 nM; PAK3, IC50=99 nM)[1]. PF-3758309 inhibits the growth of a panel of tumor cell lines that are anchorage-independent (IC50=4.7 nM) as well as the phosphorylation of the PAK4 substrate GEF-H1 (IC50=1.3 nM) in cells[1]. Moreover, PF-3758309 prevents HCT116 cells from accumulating endogenous pGEF-H1. PF-3758309 significantly suppresses A549 cell growth that is anchorage-independent (IC50=27 nM) and proliferation (IC50=20 nM)[1].
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| ln Vivo |
In HCT116 and A549 models, PF-3758309 (7.5-30 mg/kg; po; twice daily for 9–18 days) causes a statistically significant tumor growth inhibition (TGI)[1].
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| Animal Protocol |
Animal/Disease Models: Female nu/nu, CRL breed 6–8 weeks old mice (bearing HCT116 and A549 tumors)[1]
Doses: 7.5-30 mg/kg Route of Administration: Oral administration; twice (two times) daily for 9-18 days Experimental Results: Significant tumor growth inhibition (TGI) in HCT116 and A549 models . |
| 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. |
| Molecular Formula |
C25H30N8OS
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| Molecular Weight |
490.62
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| CAS # |
898044-15-0
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| Related CAS # |
PF-3758309 hydrochloride;1279034-84-2;PF-3758309 dihydrochloride
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| SMILES |
S1C([H])=C([H])C2=C1C(=NC(C([H])([H])[H])=N2)N([H])C1C2C([H])([H])N(C(N([H])[C@@]([H])(C3C([H])=C([H])C([H])=C([H])C=3[H])C([H])([H])N(C([H])([H])[H])C([H])([H])[H])=O)C(C([H])([H])[H])(C([H])([H])[H])C=2N([H])N=1
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| InChi Key |
AYCPARAPKDAOEN-LJQANCHMSA-N
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| InChi Code |
InChI=1S/C25H30N8OS/c1-15-26-18-11-12-35-20(18)23(27-15)29-22-17-13-33(25(2,3)21(17)30-31-22)24(34)28-19(14-32(4)5)16-9-7-6-8-10-16/h6-12,19H,13-14H2,1-5H3,(H,28,34)(H2,26,27,29,30,31)/t19-/m1/s1
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| Chemical Name |
(S)-N-(2-(dimethylamino)-1-phenylethyl)-6,6-dimethyl-3-((2-methylthieno[3,2-d]pyrimidin-4-yl)amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide.
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| Synonyms |
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.10 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.10 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.10 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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Structural characterization of PF-3758309 binding to the PAK4 catalytic domain.Proc Natl Acad Sci U S A.2010 May 18;107(20):9446-51. |
Tumor growth inhibition of human xenograft tumor models.
PF-3758309 is antiproliferative and induces apoptosis in a HCT116 tumor model.Proc Natl Acad Sci U S A.2010 May 18;107(20):9446-51. |
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