AZD8055 --- mTOR Inhibitor

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 evaluated in a phase I clinical study in patients with advanced tumors.

Product information

CAS Number: 1009298-09-2

Molecular Weight: 465.54

Formula: C25H31N5O4

Chemical Name: (5-(2,4-bis((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-2-methoxyphenyl)methano

Smiles: COC1=CC=C(C=C1CO)C1=CC=C2C(N=C(N=C2N2CCOC[C@@H]2C)N2CCOC[C@@H]2C)=N1

InChiKey: KVLFRAWTRWDEDF-IRXDYDNUSA-N

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

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO up to 100 mM

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

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.

References:

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.

Products are for research use only. Not for human use.

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