生物活性

• 靶点	mTOR IC50:0.8nM

• 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
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  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

• 更多

• 动物研究
  剂量	Mice20028854 (p.o.): min = 2.5 mg/kg, max = 20 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Dogs[3] Dose 1 mg/kg Administration i.g. Cmax 228 ± 39.2 ng/ml T1/2 4.5 ± 0.7 h AUC 787 ± 108.5 ng/ml·h MRT 3.1 ± 0.5 h

• 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... more >>ed Hepatocellular Carcinoma Collapse <<	Phase 1	Completed	-	Hong Kong ... more >> Research Site Hong Kong, Hong Kong Korea, Republic of Research Site Seongnam, Gyeonggi-do, Korea, Republic of Research Site Seoul, Korea, Republic of Collapse <<
  NCT01194193	Cancer Advanc... more >>ed Solid Tumours Lymphomas Collapse <<	Phase 1	Withdrawn(Amendment to study c... more >>ompound development programme) Collapse <<	-	-
  NCT00973076	Cancer Solid ... more >>Tumors Advanced Solid Malignancies Collapse <<	Phase 1	Completed	-	Japan ... more >> Research Site Tokyo, Japan Collapse <<

• 更多
• 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.