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AZD-8055

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Chemical Structure| 1009298-09-2 同义名 : CCG-168
CAS号 : 1009298-09-2
货号 : A224432
分子式 : C25H31N5O4
纯度 : 99%+
分子量 : 465.545
MDL号 : MFCD16660191
存储条件：

粉末 Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 35 mg/mL(75.18 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+35% PEG300+water 4 mg/mL clear

PO 0.5% CMC-Na 42 mg/mL suspension

生物活性
靶点

  • mTOR

    mTOR (truncated), IC50:0.13 nM

    mTOR (full length), IC50:0.8 nM
描述 The kinase mTOR, belonging to the PIKKs family, can form two distinct multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, cell survival, and autophagy. AZD8055 is a second generation inhibitor of mTOR with IC50 against mTOR of 0.13 nM/0.8 nM (measured with truncated recombinant mTOR enzyme and native mTOR enzyme complexes extracted from HeLa cells, respectively), showing excellent selectivity (∼1,000-fold) against all class PI3K isoforms and other PIKKs members[1]. Different from rapamycin, which may activate AKT signaling as a consequence of inhibition of the negative feedback loop downstream of mTORC1[2], treatment with AZD8055 at 0 to 1280 nM can significantly inhibit pAKT-S473, p70S6K and 4E-BP1 Thr37/46 in a dose dependent manner in HEK293 or MCF-7. This shows AZD8055 can inhibit mTORC1 and mTORC2 while preventing feedback to AKT. AZD8055 can inhibit 50% proliferation on the concentration of 53 nM in U87MG, 50 nM in A549 and 20 nM in H838. Also 1 μM AZD8055 can increase LC3-II levels in the presence of E64d/leupeptin, which shows the autophagy induced by the compound in A549 and H838 cells. In U87-MG and A549 xenografts, 10 mg/kg treatment of AZD8055 orally can induce a pharmacodynamic effect on both pS6 and pAKT-s473 (decrease to 5% after 20 min and >50% for at least 8 hours later). Consistent with that, four daily doses of 20 mg/kg AZD8055 shows the significant antiproliferative effect in that model[1].
作用机制 AZD8055 binds to the ATP binding cleft of mTOR kinase[1].
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
22RV1 Growth Inhibition Assay IC50=0.70717 μM SANGER
293T 20 nM Function Assay 3 h disrupts Akt-mediated TIF-IA stability, translocation, and activity 24363449
5637 Growth Inhibition Assay IC50=1.77268 μM SANGER
临床研究
NCT号 适应症或疾病 临床期 招募状态 预计完成时间 地点
NCT00999882 Cancer Advanc... 展开 >>ed Hepatocellular Carcinoma 收起 << Phase 1 Completed - Hong Kong ... 展开 >> Research Site Hong Kong, Hong Kong Korea, Republic of Research Site Seongnam, Gyeonggi-do, Korea, Republic of Research Site Seoul, Korea, Republic of 收起 <<
NCT01194193 Cancer Advanc... 展开 >>ed Solid Tumours Lymphomas 收起 << Phase 1 Withdrawn(Amendment to study c... 展开 >>ompound development programme) 收起 << - -
NCT00973076 Cancer Solid ... 展开 >>Tumors Advanced Solid Malignancies 收起 << Phase 1 Completed - Japan ... 展开 >> Research Site Tokyo, Japan 收起 <<
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.15mL

0.43mL

0.21mL

10.74mL

2.15mL

1.07mL

21.48mL

4.30mL

2.15mL
参考文献

[1]Chresta CM, Davies BR, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 2010 Jan 1;70(1):288-98.

[2]Sarbassov DD, Ali SM, et al. Growing roles for the mTOR pathway. Curr Opin Cell Biol. 2005 Dec;17(6):596-603. Epub 2005 Oct 13.

[3]Liu Y, Xia Q, et al. Design and synthesis of alkyl substituted pyridino[2,3-D]pyrimidine compounds as PI3Kα/mTOR dual inhibitors with improved pharmacokinetic properties and potent in vivo antitumor activity. Bioorg Med Chem. 2018 Aug 7;26(14):3992-4000.