EasySep™小鼠TIL（CD45）正选试剂盒
产品号 #73152_C
PI3K/AKT通路抑制剂；抑制I类PI3k
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总览
GDC-0941是磷脂酰肌醇-4,5-二磷酸3激酶（PI3K）的抑制剂。它通过在ATP结合口袋附近结合，抑制PI3K的I类催化亚基p110α、β、δ和γ，IC₅₀值分别为3、33、3和75 nM (Folkes等人；Berndt 等人)。对II、III、IV类PI3K亚型也有选择性，但有效性较低；例如，它对II类磷脂酰肌醇-4-磷酸3-激酶C2结构域β亚基（C2β）和 IV 类的哺乳动物雷帕霉素靶蛋白（mTOR）的抑制作用在高纳摩尔浓度范围内，而对其他大多数 PI3K 亚型的抑制作用则在微摩尔范围内（Folkes 等人）。
癌症研究
·在体外和小鼠异种移植模型中，抑制多种癌细胞系的增殖，如U87MG（胶质母细胞瘤）、PC3（前列腺）和MDA-MB-361（乳腺）细胞系（Folkes等人；雷诺等人；O 'Brien等人)。
·与MAP/ERK激酶（MEK）抑制剂GDC-0973联合使用时，可诱导细胞凋亡并抑制异种移植物肿瘤生长（Hoeflich等人）。
细胞类型
癌细胞及细胞系
种属
人，小鼠，非人灵长类，其他物种，大鼠
研究领域
癌症
CAS 编号
957054-30-7
化学式
C₂₃H₂₇N₇O₃S₂
纯度
≥98%
通路
PI3K/AKT
靶点
PI3K
产品说明书及文档
请在《产品说明书》中查找相关支持信息和使用说明，或浏览下方更多实验方案。
相关材料与文献
技术资料 (2)
文献 (6)
The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer .
Journal of medicinal chemistry 2008
Abstract
Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis,biological activity,and further profiling of these compounds are described. This work resulted in the discovery of 17,GDC-0941,which is a potent,selective,orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.
Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941.
Molecular cancer therapeutics 2009
Abstract
The phosphatidylinositide 3-kinase pathway is frequently deregulated in human cancers and inhibitors offer considerable therapeutic potential. We previously described the promising tricyclic pyridofuropyrimidine lead and chemical tool compound PI-103. We now report the properties of the pharmaceutically optimized bicyclic thienopyrimidine derivatives PI-540 and PI-620 and the resulting clinical development candidate GDC-0941. All four compounds inhibited phosphatidylinositide 3-kinase p110alpha with IC(50) textless or = 10 nmol/L. Despite some differences in isoform selectivity,these agents exhibited similar in vitro antiproliferative properties to PI-103 in a panel of human cancer cell lines,with submicromolar potency in PTEN-negative U87MG human glioblastoma cells and comparable phosphatidylinositide 3-kinase pathway modulation. PI-540 and PI-620 exhibited improvements in solubility and metabolism with high tissue distribution in mice. Both compounds gave improved antitumor efficacy over PI-103,following i.p. dosing in U87MG glioblastoma tumor xenografts in athymic mice,with treated/control values of 34% (66% inhibition) and 27% (73% inhibition) for PI-540 (50 mg/kg b.i.d.) and PI-620 (25 mg/kg b.i.d.),respectively. GDC-0941 showed comparable in vitro antitumor activity to PI-103,PI-540,and PI-620 and exhibited 78% oral bioavailability in mice,with tumor exposure above 50% antiproliferative concentrations for textgreater8 hours following 150 mg/kg p.o. and sustained phosphatidylinositide 3-kinase pathway inhibition. These properties led to excellent dose-dependent oral antitumor activity,with daily p.o. dosing at 150 mg/kg achieving 98% and 80% growth inhibition of U87MG glioblastoma and IGROV-1 ovarian cancer xenografts,respectively. Together,these data support the development of GDC-0941 as a potent,orally bioavailable inhibitor of phosphatidylinositide 3-kinase. GDC-0941 has recently entered phase I clinical trials.
The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.
Nature chemical biology 2010
Abstract
Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer,diabetes,thrombosis,rheumatoid arthritis and asthma. Recently,small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors,we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.
更多信息
| 物种 | 人, 其它物种, 大鼠, 小鼠, 非人灵长类 |
|---|---|
| Cas Number | 957054-30-7 |
| Chemical Formula | C₂₃H₂₇N₇O₃S₂ |
| 纯度 | ≥ 98% |
| Target | PI3K |
| Pathway | PI3K/AKT |
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