Product Information
| Chemical Name: |
(5-(2,4-bis((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-2-methoxyphenyl)methano |
| Molecular Weight: |
465.54 |
| Formula: |
C25H31N5O4 |
| Purity: |
≥ 98% |
| CAS#: |
1009298-09-2 |
| Solubility: |
DMSO up to 100 mM |
| Storage: |
Powder: 4oC 1 year
DMSO: 4oC 3 month
-20oC 1 year |
Biological Activity:
AZD8055 is a highly potent, selective and ATP-competitive mTOR inhibitor (IC50
= 0.8 nM). It has >1,000-fold selectivity against all PI3K isoforms
(α, β, γ, δ) and other members of the PI3K-like kinase family (ATM and
DNA-PK). It has no significant activity against a panel of 260 kinases
at concentrations up to 10 µM. AZD8055 inhibits the phosphorylation of
mTORC1 downstream targets (p70S6K and 4E-BP1) as well as phosphorylation
of the mTORC2 downstream proteins (e.g., Akt). 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 of U87MG, A549 and
H838 cells with IC50 of 53, 50, and 20 nM, respectively. It
also induces autophagy and increases 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. It also 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 was previously evalsuated
in a phase I clinical study in patients with advanced tumors.
How to Use:
In vitro: AZD8055 was used at 2.5 µM concentration in vitro and cellular assays.
In vivo: AZD8055 was orally dosed to mice at 2.5-20 mg/kg once or twice per day to inhibit tumor growth.
Reference:
- 1. Chresta CM, 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. (2010) Cancer
Res. 70(1):288-98.
- 2. García-Martínez JM, et al. Effect of PI3K- and mTOR-specific
inhibitors on spontaneous B-cell follicular lymphomas
in PTEN/LKB1-deficient mice. (2011) Br J Cancer. 104(7):1116-25.
- 3. Jiang Q, et al. mTOR kinase inhibitor AZD8055 enhances the
immunotherapeutic activity of an agonist CD40 antibody in cancer
treatment.(2011) Cancer Res. 71(12):4074-84.
- 4. Huang S, et al. Inhibition of mTOR kinase by AZD8055 can
antagonize chemotherapy-induced cell death through autophagy induction
and down-regulation of p62/sequestosome 1. (2011) J Biol
Chem. 286(46):40002-12.
- 5. Willems L, et al. The dual mTORC1 and mTORC2 inhibitor AZD8055
has anti-tumor activity in acute myeloid leukemia. (2012) Leukemia.
26(6):1195-202.
- 6. Holt SV, et al. Enhanced apoptosis and tumor growth suppression
elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors
(AZD8055). (2012) Cancer Res. 72(7):1804-13.
- 7. Naing A, et al. Safety, tolerability, pharmacokinetics and
pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma.
(2012) Br J Cancer. 107(7):1093-9.
- 8. Pike KG, et al. Optimization of potent and selective dual mTORC1
and mTORC2 inhibitors: The discovery of AZD8055 and AZD2014. (2013)
Bioorg Med Chem Lett. In press.
Products are for research use only. Not for human use.
