PF-3758309

PAK4 inhibitor CAS# 898044-15-0

PF-3758309

Catalog No. BCC1853----Order now to get a substantial discount!

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Chemical structure

PF-3758309

3D structure

Chemical Properties of PF-3758309

Cas No. 898044-15-0 SDF Download SDF
PubChem ID 25227462 Appearance Powder
Formula C25H30N8OS M.Wt 490.62
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 100 mg/mL (203.82 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide
SMILES CC1=NC2=C(C(=N1)NC3=NNC4=C3CN(C4(C)C)C(=O)NC(CN(C)C)C5=CC=CC=C5)SC=C2
Standard InChIKey AYCPARAPKDAOEN-LJQANCHMSA-N
Standard InChI 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
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of PF-3758309

DescriptionPF-03758309 is a potent, ATP-competitive, pyrrolopyrazole inhibitor of PAK4 with IC50 of 1.3 nM.
TargetsPAK4    
IC50Ki=18.7 nM, Kd = 2.7 nM     

Protocol

Cell Assay [3]
CCK-8 assay is performed to determine cell viability. Cells are seeded at a density of 104 cells per well into 96-well plates with 10 % fetal bovine serum and incubated for 24 h. Then, cells are treated with PF-3758309 at various concentrations (0, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, and 30 μM) for 3 days. After the exposure period, the medium is changed and incubated with CCK-8 solution (10 % of the total volume)/well for 30 min. The medium is measured spectrophotometrically at 450 nm and the percentage of viable cells is estimated by comparison with the 0.3 % DMSO control cells.

Animal Administration [4]
Five- to six-week-old female athymic nude mice are used. Mice are caged in five groups and kept on a 12-h light/dark cycle and provided with sterilized food and water ad libitum. Animals are allowed to acclimate for at least 7 days before any handling. All CRC cells are harvested in exponential phase growth and resuspended in a 1:1 mixture of serum-free RPMI 1640 and Matrigel. Five to ten million cells per mouse are injected s.c. into the flank using a 23-gage needle. Mice are monitored daily for signs of toxicity and are weighed twice weekly. Tumor size is evaluated twice per week by caliper measurements using the following formula: tumor volume=length×width2×0.52. When tumors reached 150-300 mm3 mice are randomized into two groups with at least 10 tumors per group. Mice are then treated for 14 days with either vehicle control (0.5% methylcellulose), or PF-3758309 (25 mg/kg) twice daily by oral gavage.

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.

PF-3758309 Dilution Calculator

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Preparing Stock Solutions of PF-3758309

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.0382 mL 10.1912 mL 20.3824 mL 40.7647 mL 50.9559 mL
5 mM 0.4076 mL 2.0382 mL 4.0765 mL 8.1529 mL 10.1912 mL
10 mM 0.2038 mL 1.0191 mL 2.0382 mL 4.0765 mL 5.0956 mL
50 mM 0.0408 mL 0.2038 mL 0.4076 mL 0.8153 mL 1.0191 mL
100 mM 0.0204 mL 0.1019 mL 0.2038 mL 0.4076 mL 0.5096 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on PF-3758309

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 confirmed that PF-3758309 modulates PAK4-dependent signaling nodes and identifies 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.

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References on PF-3758309

Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth.[Pubmed:20439741]

Proc Natl Acad Sci U S A. 2010 May 18;107(20):9446-51.

Despite abundant evidence that aberrant Rho-family GTPase activation contributes to most steps of cancer initiation and progression, there is a dearth of inhibitors of their effectors (e.g., p21-activated kinases). Through high-throughput screening and structure-based design, we identify PF-3758309, a potent (K(d) = 2.7 nM), ATP-competitive, pyrrolopyrazole inhibitor of PAK4. 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 +/- 3 nM). The molecular underpinnings of PF-3758309 biological effects were characterized using an integration of traditional and emerging technologies. Crystallographic characterization of the PF-3758309/PAK4 complex defined determinants of potency and kinase selectivity. Global high-content cellular analysis confirms that PF-3758309 modulates known PAK4-dependent signaling nodes and identifies unexpected links to additional pathways (e.g., p53). In tumor models, PF-3758309 inhibits PAK4-dependent pathways in proteomic studies and regulates functional activities related to cell proliferation and survival. PF-3758309 blocks the growth of multiple human tumor xenografts, with a plasma EC(50) value of 0.4 nM in the most sensitive model. This study defines PAK4-related pathways, provides additional support for PAK4 as a therapeutic target with a unique combination of functions (apoptotic, cytoskeletal, cell-cycle), and identifies a potent, orally available small-molecule PAK inhibitor with significant promise for the treatment of human cancers.

Tumor P-Glycoprotein Correlates with Efficacy of PF-3758309 in in vitro and in vivo Models of Colorectal Cancer.[Pubmed:23524533]

Front Pharmacol. 2013 Mar 22;4:22.

P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter family, is overexpressed in a number of different cancers and some studies show that P-gp overexpression can be correlated to poor prognosis or therapeutic resistance. Here we sought to elucidate if PF-3758309 (PF-309), a novel p-21 activated kinase inhibitor, efficacy was influenced by tumor P-gp. Based on in vitro proliferation data, a panel of colorectal cancer cell lines were ranked as sensitive or resistant and ABCB1 (P-gp) expression was evaluated by microarray for these cell lines. P-gp expression was determined by western blot and activity determined by rhodamine efflux assay. Knock down of P-gp and pharmacologic inhibition of P-gp to restore PF-309 activity was performed in vitro. PF-309 activity was evaluated in vivo in cell line xenograft models and in primary patient derived tumor xenografts (PDTX). Mice were treated with 25 mg/kg PF-309 orally, twice daily. On the last day of treatment, tumor and plasma were collected for PF-309 analysis. Here we show that ABCB1 gene expression correlates with resistance to PF-309 treatment in vitro and the expression and activity of P-gp was verified in a panel of resistant cells. Furthermore, inhibition of P-gp increased the sensitivity of resistant cells, resulting in a 4-100-fold decrease in the IC50s. Eleven cell line xenografts and 12 PDTX models were treated with PF-309. From the cell line xenografts, we found a significant correlation between ABCB1 gene expression profiles and tumor response. We evaluated tumor and plasma concentrations for eight tumor models (three cell line xenografts and five PDTX models) and a significant correlation was found between tumor concentration and response. Additionally, we show that tumor concentration is approximately fourfold lower in tumors that express P-gp, verified by western blot. Our in vitro and in vivo data strongly suggests that PF-309 efficacy is influenced by the expression of tumor P-gp.

Association of the epithelial-to-mesenchymal transition phenotype with responsiveness to the p21-activated kinase inhibitor, PF-3758309, in colon cancer models.[Pubmed:23543898]

Front Pharmacol. 2013 Mar 28;4:35.

The p21-activated kinase (PAK) family of serine/threonine kinases, which are overexpressed in several cancer types, are critical mediators of cell survival, motility, mitosis, transcription, and translation. In the study presented here, we utilized a panel of colorectal cancer (CRC) cell lines to identify potential biomarkers of sensitivity or resistance that may be used to individualize therapy to the PAK inhibitor PF-03758309. We observed a wide range of proliferative responses in the CRC cell lines exposed to PF-03758309, this response was recapitulated in other phenotypic assays such as anchorage-independent growth, three-dimensional (3D) tumor spheroid formation, and migration. Interestingly, we observed that cells most sensitive to PF-03758309 exhibited up-regulation of genes associated with a mesenchymal phenotype (CALD1, VIM, ZEB1) and cells more resistant had an up-regulation of genes associated with an epithelial phenotype (CLDN2, CDH1, CLDN3, CDH17) allowing us to derive an epithelial-to-mesenchymal transition (EMT) gene signature for this agent. We assessed the functional role of EMT-associated genes in mediating responsiveness to PF-3758309, by targeting known genes and transcriptional regulators of EMT. We observed that suppression of genes associated with the mesenchymal phenotype conferred resistance to PF-3758309, in vitro and in vivo. These results indicate that PAK inhibition is associated with a unique response phenotype in CRC and that further studies should be conducted to facilitate both patient selection and rational combination strategies with these agents.

PF-3758309, p21-activated kinase 4 inhibitor, suppresses migration and invasion of A549 human lung cancer cells via regulation of CREB, NF-kappaB, and beta-catenin signalings.[Pubmed:24366569]

Mol Cell Biochem. 2014 Apr;389(1-2):69-77.

Migration and invasion comprise key steps in cancer metastasis. Through the migration and invasion into and out of lymphatic and/or blood vessels, cancer cells can be spread out into the tissues in remote site from the origin. Degradation of extracellular matrix (ECM) must be preceded prior to the metastasis of cancer cells. Matrix metalloproteinases (MMP) can degrade ECM, thus allow cells to migrate from the original site. Among MMPs, two gelatinase MMP-2 and MMP-9 play particularly important roles in ECM degradation. Here, we report that recently developed p21-activated kinase 4 inhibitor PF-3758309 shows anti-metastatic effect in A549 human lung cancer cell. PF-3758309 suppresses CREB, NF-kappaB, and beta-catenin pathways, which are well known to be closely related with cell migration. This leads to the downregulation of MMP-2/MMP-9 expressions and the inhibition of A549 lung cancer metastasis.

Description

PF-3758309 is a potent, orally available, and reversible ATP-competitive inhibitor of PAK4 (Kd= 2.7 nM; Ki=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.

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