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AZD-8055 CAS: 1009298-09-2

Category: Inhibitors
Product Name: AZD-8055
Cat No: I000106
CAS No: 1009298-09-2
Synonyms: [5-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxyphenyl]methanol
Molecular Formula: C25H31N5O4
Molecular Weight: 465.5
SMILES: C[C@@H](COCC1)N1C2=NC(N3[C@@H](C)COCC3)=C(C=CC(C4=CC(CO)=C(OC)C=C4)=N5)C5=N2
InChI: InChI=1S/C25H31N5O4/c1-16-14-33-10-8-29(16)24-20-5-6-21(18-4-7-22(32-3)19(12-18)13-31)26-23(20)27-25(28-24)30-9-11-34-15-17(30)2/h4-7,12,16-17,31H,8-11,13-15H2,1-3H3/t16-,17-/m0/s1
Solubility: DMSO ≥90mg/mL Water ≥1.8mg/mL Ethanol ≥13mg/mL
Target: mTOR
IC50: 0.8 nM
Storage: powder
CAS 1009298-09-2,AZD-8055
  • Description

AZD8055 is a novel ATP-competitive mTOR inhibitor with IC50 of 0.8 nM with excellent selectivity (~1,000-fold) against PI3K isoforms and ATM/DNA-PK.

in vitro: AZD8055 shows low activity (~1,000-fold) against all PI3K isoforms (α, β, γ, δ) and other members of the PI3K-like kinase family (ATM and DNA-PK). AZD8055 inhibits the phosphorylation of mTORC1 (p70S6K and 4E-BP1) as well as phosphorylation of the mTORC2 (Akt) and downstream proteins. The rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1 can be fully inhibited by AZD8055, resulting in significant inhibition of cap-dependent translation. AZD8055 potently inhibits proliferation in U87MG, A549 and H838 cells with IC50 of 53, 50 and 20 nM, respectively. AZD8055 also induces autophagy and increased LC3-II levels in H838 and A549 cells . AZD8055 decreases AML blast cell proliferation and cell cycle progression, reduces the clonogenic growth of leukemic progenitors and induces caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells. 

in vivo: AZD8055 inhibits the pS6 and pAkt in U87MG and A549 xenografts at 2.5/10 mg/kg, which leads to tumor growth inhibition. AZD8055 shows significant antitumor activity in many xenografts, including U87MG, BT474c, A549, Calu-3, LoVo, SW620, PC3 and MES-SA at a dose of 10/20 mg/kg . AZD8055 induces ~40% reduction in tumour volume, accompanied by ablation of phosphorylation of Akt, S6K and SGK protein kinases. Administration of AZD8055 (5mg/kg, Bid) and SAHA (100 mg/kg/d) results in complete tumor growth inhibition in PTEN+/LKB1+/hypo xenografts without side effects on mice by inhibition of mTORC1 and mTORC2 signaling.

  • Spec

Appearance:Yellow solid powder
Purity: > 98%

  • References

1:Tumour Biol. 2016 Aug;37(8):11039-48. doi: 10.1007/s13277-015-4598-1. Epub 2016 Feb 20. C6 ceramide sensitizes the anti-hepatocellular carcinoma (HCC) activity by AZD-8055, a novel mTORC1/2 dual inhibitor.Liu M,Gu P,Guo W,Fan X, PMID: 26897748 DOI: 10.1007/s13277-015-4598-1
Abstract: Aberrant activation of mammalian target of rapamycin (mTOR) plays pivotal roles in promoting hepatocellular carcinoma (HCC) tumorigenesis and chemoresistance. Here, we tested the potential anti-HCC activity by a novel mTOR complex 1/2 (mTORC1/2) dual inhibitor AZD-8055 and, more importantly, the potential AZD-8055 sensitization effect by a cell-permeable short-chain ceramide (C6). We showed that AZD-8055 mainly exerted moderate cytotoxic effect against a panel of HCC cell lines (HepG2, Hep3B, and SMMC-7721). Co-treatment of C6 ceramide remarkably augmented AZD-8055-induced HCC cytotoxicity. Meanwhile, C6 ceramide dramatically potentiated AZD-8055-induced HCC cell apoptotic death. Further studies demonstrated that AZD-8055 and C6 ceramide synergistically induced anti-survival and pro-apoptotic activity in primary cultured human HCC cells, but not in the non-cancerous human hepatocytes. Signaling studies showed that AZD-8055 and C6 ceramide synergistically suppressed Akt-mTOR complex 1/2 cascade activation. In vivo, AZD-8055 oral administration suppressed HepG2 hepatoma xenograft growth in nude mice, while moderately improving mice survival. Its anti-tumor activity was dramatically potentiated with co-administration of a liposome-packed C6 ceramide. Together, these results demonstrate that concurrent targeting mTORC1/2 by AZD-8055 exerts anti-tumor ability in preclinical HCC models, and its activity is further sensitized with co-administration of C6 ceramide.

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