Glasdegib-PF-04449913-DataSheet-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEGlasdegibCat. No.: HY-16391CAS No.: 1095173-27-5Synonyms: PF-04449913分式: CHNO分量: 374.44作靶點: Smo作通路: Stem Cell/Wnt儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 83.33 mg/mL (222.55 mM)* mea

2、ns soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 2.6707 mL 13.3533 mL 26.7065 mL5 mM 0.5341 mL 2.6707 mL 5.3413 mL10 mM 0.2671 mL 1.3353 mL 2.6707 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲備液，并請注意儲備液的保存式和期限。體內實驗請根據(jù)您的實驗動物和給藥式選擇適當?shù)娜芙獍?，配制前請先配制澄清的儲備液，再依次添加助溶?為保證實驗結果的可靠性，體內實驗的作液，建

3、議您現(xiàn)現(xiàn)配，當天使；澄清的儲備液可以根據(jù)儲存條件，適當保存；以下溶劑前的百分 指該溶劑在您配制終溶液中的體積占)：1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.08 mg/mL (5.55 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.08 mg/mL (5.55 mM); Clear solution1/3 Master of Small Molecules 您邊的抑制劑師www.M

4、edChemE3. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.08 mg/mL (5.55 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Glasdegib (PF-04449913)種服有效的 smoothened 抑制劑。Glasdegib (PF-04449913) 結合到 SMO(181-787氨基酸位點)，IC50 為 4 nM。IC50 & Target IC50: 4 nM (Smo) 1體外研究 Glasdegib (PF-04449913) inhibits sonic hedgehog

5、(Shh) stimulated luciferase expression in mouseembryonic fibroblasts with an IC50 of 6.8 nM; and significantly reduces medulloblastoma growth in a Ptch1+/-p53+/- allograft model at doses that decreased murine Shh target gene expression. In stromal co-cultureexperiments, FACS analysis demonstrates a

6、significant reduction in BC LSC by Glasdegib (PF-04449913)when compared with normal progenitors. Importantly, human BC LSC engrafted RAG2-/-C-/- mice treateddaily with Glasdegib (PF-04449913) compared with vehicle treated controls have a significant spleen weightreduction (p=0.006). This reduction i

7、n leukemic burden corresponded with decreased GLI2 proteinexpression, as determined by both nanoproteomic analysis of FACS purified human progenitors and GLI2confocal fluorescence microscopic analysis of splenic sections 1.體內研究 Human BC LSC engrafted RAG2-/-C-/- mice treated daily with Glasdegib (PF

8、-04449913) compared withvehicle treated controls had a significant spleen weight reduction (p=0.006). When CD34+ cord bloodengrafted NSG mice are treated with Glasdegib (PF-04449913), the frequency of human CD45+ cells,progenitors and both myeloid and lymphoid cell fate commitment remained comparabl

9、e to vehicle treatedcontrols indicating that unlike LSC, normal human HSC cell fate decisions are Hh pathway independent.These results highlight the important niche dependent effects of selective SMO inhibition that induce GLI2downregulation in a cell type and context specific manner 1.PROTOCOLCell

10、Assay 1 Normal or BC CML CD34+ cells are plated on confluent mitomycin-C treated SL/M2 cells with vehicle,Glasdegib (PF-04449913) (1 M), Dasatinib (50 nM), or combination treatment. Mouse bone marrow stromalcell lines, M2-10B4 (M2) and SL/SL (SL) are treated with mitomycin-C (1 mg/mL) and plated in

11、a 1:1 mixtureat a total concentration of 100,000 cells/mL one day prior to co-culture with 10,000-20,000 CD34+ BC CMLor normal progenitors. After 1 week of culture, progenitors are FACS sorted into hematopoietic progenitorassays and colonies are scored at 14 days. To assess survival of normal human

12、hematopoietic stem andprogenitor cells, irradiated (20 Gray) OP9 (M2 clone) stromal cells are co-cultured with 50,000 human CD34+cord blood cells, vehicle or Glasdegib (PF-04449913) in AlphaMEM with 20% Hyclone FBS, 1% pen strepglutamine and supplemented with 50 ng/mL SCF, 10 ng/mL thrombopoietin, a

13、nd 10 ng/mL Flt3 andquantified by weekly FACS analysis 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEAnimal Mice 1Administration 1 RAG2-/-c-/- mice are transplanted intrahepatically with equal numbers

14、 of normal progenitors or BC LSC.Upon detection of human CD45+ cell peripheral blood engraftment, mice are treated daily by oral gavagewith vehicle (50% 1,2 Propandiol, 50% HBSS or methylcellulose), Glasdegib (100 mg/kg), Dasatinib (50mg/kg), or the combination for 14 days followed by FACS to quanti

15、fy human engraftment in hematopoieticniches. To assess effects on normal HSC function, 7 to 10 week old NOD. Cg-PrkdcSCID IL2R1Wjl/SzJ miceare sublethally irradiated, transplanted retro-orbitally with 100,000 CD34+ human cord blood cells and treated8 weeks later with vehicle or Glasdegib (100 mg/kg)

16、 for 14 days followed by FACS engraftment analysis.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻 Methods Mol Biol. 2018;1711:351-398.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Sadarangani A, et al. GLI2 inhibition abrogates human leukemia stem cell