| CAS |
No.1095173-27-5 |
| 中文名称 |
格拉吉布 |
| 英文名称 |
Glasdegib |
| 别名 |
;Glasdegib;UNII-K673DMO5H9; |
| 分子式 |
C21H22N6O |
| 分子量 |
374.44 |
| 溶解性 |
Soluble in DMSO ≥5mg/mL(Need ultrasonic) |
| 纯度 |
≥98% |
| 外观(性状) |
White to off-white Solid |
| 储存条件 |
Powder:2-8℃，2 years;Insolvent(母液):-20℃，6 months;-80℃，1 year |
| 运输条件 |
冷藏运输 |
| MDL |
MFCD29037212 |
| SMILES |
O=C(NC1=CC=C(C#N)C=C1)N[C@H]2C[C@H](C3=NC4=CC=CC=C4N3)N(C)CC2 |
| InChIKey |
SFNSLLSYNZWZQG-VQIMIIECSA-N |
| InChI |
InChI=1S/C21H22N6O/c1-27-11-10-16(24-21(28)23-15-8-6-14(13-22)7-9-15)12-19(27)20-25-17-4-2-3-5-18(17)26-20/h2-9,16,19H,10-12H2,1H3,(H,25,26)(H2,23,24,28)/t16-,19-/m1/s1 |
| PubChem CID |
25166913 |
| 靶点 |
Smo |
| 通路 |
Hedgehog;Stem Cells |
| 背景说明 |
Glasdegib是一种有效的 smoothened 抑制剂。 |
| 生物活性 |
Glasdegib (PF-04449913) is a potent and orally bioavailable smoothened inhibitor. Glasdegib (PF-04449913) binds to human SMO (amino acids 181-787) with an IC50 of 4 nM.[1] |
| IC50 |
IC50: 4 nM (Smo)[1] |
| In Vitro |
Glasdegib (PF-04449913) inhibits sonic hedgehog (Shh) stimulated luciferase expression in mouse embryonic 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-culture experiments， FACS analysis demonstrates a significant reduction in BC LSC by Glasdegib (PF-04449913) when compared with normal progenitors. Importantly， human BC LSC engrafted RAG2-/-γC-/- mice treated daily with Glasdegib (PF-04449913) compared with vehicle treated controls have a significant spleen weight reduction (p=0.006). This reduction in leukemic burden corresponded with decreased GLI2 protein expression， as determined by both nanoproteomic analysis of FACS purified human progenitors and GLI2 confocal fluorescence microscopic analysis of splenic sections[1]. |
| In Vivo |
Human BC LSC engrafted RAG2-/-γC-/- mice treated daily with Glasdegib (PF-04449913) compared with vehicle treated controls had a significant spleen weight reduction (p=0.006). When CD34+ cord blood engrafted NSG mice are treated with Glasdegib (PF-04449913)， the frequency of human CD45+ cells， progenitors and both myeloid and lymphoid cell fate commitment remained comparable to vehicle treated controls 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 GLI2 downregulation in a cell type and context specific manner[1]. |
| 细胞实验 |
Normal or BC CML CD34+ cells are treated with vehicle， Glasdegib (PF-04449913) (1 μM)， BMS-354825 (50 nM)， or combination treatment. Mouse bone marrow stromal cell lines， M2-10B4 (M2) and SL/SL (SL) are plated in a 1:1 mixture at a total concentration of 100，000 cells/mL one day prior to co-culture with 10，000-20，000 CD34+ BC CML or normal progenitors. After 1 week of culture， progenitors are FACS sorted into hematopoietic progenitor assays and colonies are scored at 14 days. To assess survival of normal human hematopoietic stem and progenitor 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 strep glutamine and supplemented with 50 ng/mL SCF， 10 ng/mL thrombopoietin， and 10 ng/mL Flt3 and quantified by weekly FACS analysis[1]. |
| 动物实验 |
Mice[1] RAG2-/-c-/- mice are transplanted intrahepatically with equal numbers of normal progenitors or BC LSC. Upon detection of human CD45+ cell peripheral blood engraftment， mice are treated daily by oral gavage with vehicle (50% 1，2 Propandiol， 50% HBSS or methylcellulose)， Glasdegib (100 mg/kg)， BMS-354825 (50 mg/kg)， or the combination for 14 days followed by FACS to quantify human engraftment in hematopoietic niches. To assess effects on normal HSC function， 7 to 10 week old NOD. Cg-PrkdcSCID IL2R1Wjl/SzJ mice are sublethally irradiated， transplanted retro-orbitally with 100，000 CD34+ human cord blood cells and treated 8 weeks later with vehicle or Glasdegib (100 mg/kg) for 14 days followed by FACS engraftment analysis. |
| 数据来源文献 |
[1]. Sadarangani A， et al. GLI2 inhibition abrogates human leukemia stem cell dormancy. J Transl Med. 2015 Mar 21;13:98. |
| 规格 |
1mg 5mg 10mg 25mg 50mg |
| 单位 |
瓶 |
中文
英语
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