PF-3758309 - PAK 抑制剂 - 生命科学试剂 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEPF-3758309Cat. No.: HY-13007CAS No.: 898044-15-0分式: CHNOS分量: 490.62作靶点: PAK作通路: Cell Cycle/DNA Damage; Cytoskeleton储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 100 mg/mL (203.82 mM)* mea

2、ns soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 2.0382 mL 10.1912 mL 20.3824 mL5 mM 0.4076 mL 2.0382 mL 4.0765 mL10 mM 0.2038 mL 1.0191 mL 2.0382 mL请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存式和期限。体内实验请根据您的实验动物和给药式选择适当的溶解案，配制前请先配制澄清的储备液，再依次添加助溶剂(为保证实验结果的可靠性，体内实验的作液，建

3、议您现现配，当天使；澄清的储备液可以根据储存条件，适当保存；以下溶剂前的百分 指该溶剂在您配制终溶液中的体积占)：1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (5.10 mM); Clear solution2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (5.10 mM); Clear solution3. 请依序添加每种溶剂： 10% DMSO 90% corn oil1/3 Maste

4、r of Small Molecules 您边的抑制剂师www.MedChemESolubility: 2.5 mg/mL (5.10 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 PF-3758309种有效的 PAK 抑制剂，能够抑制 PAK4 的活性，IC50 值为 1.3 nM。IC50 & Target PAK4 PAK1 PAK5 PAK618.7 nM (Ki) 13.7 nM (Ki) 18.1 nM (Ki) 17.1 nM (Ki)体外研究 F-3758309 binds directly to PAK4 with an in vitro

5、 potency of 2.7-4.5 nM. PF-3758309 has similar enzymaticpotency against the kinase domains of the other group B PAKs (PAK5, Ki=18.15.1 nM; PAK6, Ki=17.15.3nM) and group A PAK1 (Ki=13.71.8 nM), but is less active against the other two group A PAKs (PAK2,IC50=190 nM; PAK3, IC50=99 nM). PAK4 phosphoryl

6、ates GEF-H1 on a previously characterized serineresidue 810 and is inhibited by PF-3758309 (IC50=1.30.5 nM). PF-3758309 also inhibits endogenouspGEF-H1 accumulation in HCT116 cells 1. PF-3758309 is profiled for its growth-inhibitory activity in a panelof 92 tumor cell lines, half of which exhibits I

7、C50 values of less than 10 nM 2. The proliferation of A549 cellsis affected at the treatment with lower dosage (1 M) of PF-3758309 3.体内研究 PF-3758309 (7.5-30 mg/kg BID, p.o.) results in statistically significant tumor growth inhibition (TGI) in fivemodels including HCT116 and A549 models. PF-3758309

8、(15 mg/kg BID, p.o.) is found to inhibit 3HFLTuptake 32.5% in the HCT116 tumor xenografts by day 6. PF-3758309 treatment shows a significant increasein the apoptotic marker activated caspase 3 in HCT116 tumors 1. PF-3758309 (25 mg/kg, p.o.) exhibitsantiproliferative effects on cell line xenografts 4

9、.PROTOCOLCell Assay 3 CCK-8 assay is performed to determine cell viability. Cells are seeded at a density of 104 cells per well into96-well plates with 10 % fetal bovine serum and incubated for 24 h. Then, cells are treated with PF-3758309at various concentrations (0, 0.01, 0.03, 0.1, 0.3, 1, 3, 10,

10、 and 30 M) 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. Themedium is measured spectrophotometrically at 450 nm and the percentage of viable cells is estimated bycomparison with the 0.3 % DMSO control cells.M

11、CE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Five- to six-week-old female athymic nude mice are used. Mice are caged in five groups and kept on a 12-hAdministration 4 light/dark cycle and provided with sterilized food and water ad libitum. Anim

12、als are allowed to acclimate for atleast 7 days before any handling. All CRC cells are harvested in exponential phase growth and resuspendedin a 1:1 mixture of serum-free RPMI 1640 and Matrigel. Five to ten million cells per mouse are injected o the flank using a 23-gage needle. Mice are moni

13、tored daily for signs of toxicity and are weighed twiceweekly. Tumor size is evaluated twice per week by caliper measurements using the following formula: tumorvolume=lengthwidth20.52. When tumors reached 150-300 mm3 mice are randomized into two groups withat least 10 tumors per group. Mice are then

14、 treated for 14 days with either vehicle control (0.5%2/3 Master of Small Molecules 您边的抑制剂师www.MedChemEmethylcellulose), or PF-3758309 (25 mg/kg) twice daily by oral gavage.MCE has not independently confirmed the accuracy of these methods. They are for reference only.户使本产品发表的科研献 Science. 2017 Dec 1;

15、358(6367). Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. Harvard Medical School LINCS LIBRARYSee more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Murray, Brion W., et al. Small-molecule p21-activated kinase inhibitor PF3758309 is a potent inhibitor of oncogenic signaling and t

16、umorgrowth. Proceedings of the National Academy of Sciences of the United States of America (2010), 107(20), 9446-9451, S942. 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 viaregulation of CREB, NF-B, and -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 kinaseinhibitor, PF-3758309, in