生物活性

• 靶点

  mTOR IC50:38nM

  ATR IC50:5nM

• 描述Ataxia–telangiectasia and Rad3 (ATR) is one of the two chief regulators of the DNA damage response (DDR) and plays a key role in multiple cellular functions, such as cell-cycle checkpoints, DNA repair and so on. AZ 20 is a kind of ATR-selective inhibitor with a variable IC₅₀ value from about 350 nM to 1.4 μM in the acute myeloid leukemia (AML) cell lines. Consistent with inhibition by AZ 20 on ATR, treatment with 0 – 8μM AZ20 for 24h could induce concentration-dependent apoptosis, abrogate the G2/M cell cycle checkpoint through activation of CDK1, as well as cause DNA damage by increasing the expression of RPA32 and γH2AX in the THP-1 and OCI-AML3 cells. Meanwhile, it was found that when treated with cell for 24 or 48h, AZ 20 could synergize with cytarabine and contribute to the cell death, proliferation inhibition and increase of DNA replication stress in AML cell lines. Oral gavage of 50mg/kg AZ 20 and 0.5mg/kg trametinib once daily for 14 days, could significantly delay progression of disease, reduce leukemia burden or infiltration of hematopoietic tissues and induce the apoptosis of leukemia cells in a sublethally irradiated mice model with Mll-Af4/N-Ras^G12D leukemic cells injection. However, AZ 20 alone just has transient efficacy in this model, and it's not sufficient for durably inhibiting disease progression. Additionally, similar efficacy was also observed in PDX models of human MLL-AF4 B-cell acute lymphoblastic leukemia (B-ALLs), which is suggesting that the combination of trametinib and AZ 20 is a potential treatment strategy of MLL-AF4/N-RAS B-ALLs, particularly those with high mutant RAS VAF.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  HT29 cells	-	Function assay	1 h	Inhibition of ATR-mediated CHK1 phosphorylation at serine 345 in human HT29 cells after 1 hr in presence of 4-nitroquinoline 1-oxide, IC50=0.05 μM	23394205
  human MDA-MB-468 cells	-	Function assay	-	Inhibition of mTOR-mediated AKT phosphorylation at serine 473 in human MDA-MB-468 cells, IC50=2.4 μM	23394205
  LoVo cells	-	Growth inhibition assay	72 h	Growth inhibition of human LoVo cells after 72 hrs by MTS assay, GI50=0.2 μM	23394205

• 动物研究
  剂量	Mice: 25 mg/kg, 50 mg/kg[1] (p.o.)
  给药途径	p.o.

• 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
  NCT03382197	Chronic Obstructive Pulmonary ... more >>Disease Collapse <<	Not Applicable	Active, not recruiting	November 2018	Brazil ... more >> Department of Physical Therapy, Federal University of Pernambuco, Recife, Pernambuco, Brazil Recife, Pernambuco, Brazil, 50670-901 Collapse <<
  NCT01482624	Arthroscopic Meniscal Surgery	Not Applicable	Completed	-	Belgium ... more >> AZ Monica, Orthopedisch centrum SPM Deurne, Belgium, 2100 Collapse <<
  NCT01283009	Community Acquired Respiratory... more >> Disease Syndrome Collapse <<	Phase 3	Completed	-	-

• 更多
• 参考文献

• [1] Foote KM, Blades K, et al. Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl] -6-[1-(methylsulfonyl)cyclopropyl] pyrimidin-2-yl}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity. J Med Chem. 2013 Mar 14;56(5):2125-38.