AZD-8055
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MedKoo CAT#: 200312

CAS#: 1009298-09-2

Description: AZD-8055 is an inhibitor of the mammalian target of rapamycin (mTOR) with potential antineoplastic activity. mTOR kinase inhibitor AZD8055 inhibits the serine/threonine kinase activity of mTOR, resulting in decreased expression of mRNAs necessary for cell cycle progression, which may induce cell cycle arrest and tumor cell apoptosis. mTOR phosphorylates transcription factors, such as S6K1 and 4E-BP1, which stimulate protein synthesis and regulate cell growth, proliferation, motility, and survival.


Chemical Structure

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AZD-8055
CAS# 1009298-09-2

Theoretical Analysis

MedKoo Cat#: 200312
Name: AZD-8055
CAS#: 1009298-09-2
Chemical Formula: C25H31N5O4
Exact Mass: 465.2376
Molecular Weight: 465.54
Elemental Analysis: C, 64.50; H, 6.71; N, 15.04; O, 13.75

Price and Availability

Size Price Availability Quantity
25.0mg USD 90.0 Same Day
50.0mg USD 150.0 Same Day
100.0mg USD 250.0 Same Day
200.0mg USD 450.0 Same Day
500.0mg USD 950.0 Same Day
1.0g USD 1650.0 Same Day
2.0g USD 2950.0 Same Day
5.0g USD 6450.0 2 Weeks
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Synonym: AZD8055; AZD-8055; AZD 8055.

IUPAC/Chemical Name: (5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol.

InChi Key: KVLFRAWTRWDEDF-IRXDYDNUSA-N

InChi Code: 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

SMILES Code: OCC1=CC(C2=NC3=NC(N4[C@@H](C)COCC4)=NC(N5[C@@H](C)COCC5)=C3C=C2)=CC=C1OC

Appearance: Yellow solid powder

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

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: AZD-8055 is a mTOR kinase inhibitor with an IC50 of 0.8 nM.
In vitro activity: The antitumor effect of AZD8055 on colon cancer cells was studied. The human HT-15 and HCT-116 colon cancer cell lines, and the mouse CT-26 colon cancer cell line, were treated with different concentrations of AZD8055 for 24 h or 48 h. Following this, cell viability was measured using an MTT assay (Figure 1a). AZD8055 was found to inhibit the proliferation of these three colon cancer cell lines in a time- and concentration-dependent manner (p<0.05). The LC50s for AZD8055 at 24 h and 48 h of treatment were 107.8 μM and 9.8 μM for HCT-15 cells, 124.6 μM and 21.5 μM for HCT-116 cells, and 3.0 μM and 0.43 μM for CT-26 cells, respectively. To further investigate the effect on cell viability, apoptosis induction was examined in these colon cancer cells treated with different concentrations of AZD8055 for 48 h. As shown in Figure 1b, AZD8055 treatment caused a significant, concentration-dependent increase in apoptosis of these colon cancer cells (p<0.05). Reference: Anticancer Res. 2018 Mar;38(3):1445-1454. https://ar.iiarjournals.org/content/38/3/1445.long
In vivo activity: The in vivo effect of AZD8055 on tumor growth was investigated in a CT-26 syngeneic tumor model (Figure 5). The AZD8055 treatment was given from day 1 to 28 in the early treatment group, and from day 11 to 28 in the delayed treatment group. The administration of AZD8055 did not induce a significant change in the activity or body weight of mice throughout the treatment course, and all animals survived after completion of the treatment. The early-treatment group showed a significantly slower tumor growth rate than the delayed-treatment group (tumor size on day 28: 198.3±343.8 mm3 vs. 479.6±380.9 mm3; p=0.0067) or the control group (tumor size on Day 28, 198.3±343.8 mm3 vs. 1156.8±579.1 mm3; p=0.003). In addition, the tumor growth rate also significantly differed between the delayed-treatment group and the control group was (tumor size on day 28: 479.6±380.9 mm3 vs. 1156.8±579.1 mm3; p=0.017). These data suggest that AZD8055 treatment exerts an antitumor effect on the subcutaneous CT-26 tumor in vivo, and early treatment has a better effect than delayed treatment. Reference: Anticancer Res. 2018 Mar;38(3):1445-1454. https://ar.iiarjournals.org/content/38/3/1445.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 45.44 97.61
Ethanol 10.25 22.02
DMF 10.0 21.48

Preparing Stock Solutions

The following data is based on the product molecular weight 465.54 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Chen Y, Lee CH, Tseng BY, Tsai YH, Tsai HW, Yao CL, Tseng SH. AZD8055 Exerts Antitumor Effects on Colon Cancer Cells by Inhibiting mTOR and Cell-cycle Progression. Anticancer Res. 2018 Mar;38(3):1445-1454. doi: 10.21873/anticanres.12369. PMID: 29491070. 2. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, Vincent JP, Ellston R, Jones D, Sini P, James D, Howard Z, Dudley P, Hughes G, Smith L, Maguire S, Hummersone M, Malagu K, Menear K, Jenkins R, Jacobsen M, Smith GC, Guichard S, Pass M. 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. doi: 10.1158/0008-5472.CAN-09-1751. Epub 2009 Dec 22. PMID: 20028854.
In vitro protocol: 1. Chen Y, Lee CH, Tseng BY, Tsai YH, Tsai HW, Yao CL, Tseng SH. AZD8055 Exerts Antitumor Effects on Colon Cancer Cells by Inhibiting mTOR and Cell-cycle Progression. Anticancer Res. 2018 Mar;38(3):1445-1454. doi: 10.21873/anticanres.12369. PMID: 29491070. 2. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, Vincent JP, Ellston R, Jones D, Sini P, James D, Howard Z, Dudley P, Hughes G, Smith L, Maguire S, Hummersone M, Malagu K, Menear K, Jenkins R, Jacobsen M, Smith GC, Guichard S, Pass M. 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. doi: 10.1158/0008-5472.CAN-09-1751. Epub 2009 Dec 22. PMID: 20028854.
In vivo protocol: 1. Chen Y, Lee CH, Tseng BY, Tsai YH, Tsai HW, Yao CL, Tseng SH. AZD8055 Exerts Antitumor Effects on Colon Cancer Cells by Inhibiting mTOR and Cell-cycle Progression. Anticancer Res. 2018 Mar;38(3):1445-1454. doi: 10.21873/anticanres.12369. PMID: 29491070. 2. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, Vincent JP, Ellston R, Jones D, Sini P, James D, Howard Z, Dudley P, Hughes G, Smith L, Maguire S, Hummersone M, Malagu K, Menear K, Jenkins R, Jacobsen M, Smith GC, Guichard S, Pass M. 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. doi: 10.1158/0008-5472.CAN-09-1751. Epub 2009 Dec 22. PMID: 20028854.

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1: Holt SV, Logie A, Davies BR, Alferez D, Runswick S, Fenton S, Chresta CM, Gu Y, Zhang J, Wu YL, Wilkinson RW, Guichard S, Smith PD. Enhanced apoptosis and tumor growth suppression elicited by combination of MEK and mTOR kinase inhibitors. Cancer Res. 2012 Jan 23. [Epub ahead of print] PubMed PMID: 22271687.

2: Zhang W, Khatibi NH, Yamaguchi-Okada M, Yan J, Chen C, Hu Q, Meng H, Han H, Liu S, Zhou C. Mammalian target of rapamycin (mTOR) inhibition reduces cerebral vasospasm following a subarachnoid hemorrhage injury in canines. Exp Neurol. 2011 Dec 8. [Epub ahead of print] PubMed PMID: 22177999.

3: Willems L, Chapuis N, Puissant A, Maciel TT, Green AS, Jacque N, Vignon C, Park S, Guichard S, Herault O, Fricot A, Hermine O, Moura IC, Auberger P, Ifrah N, Dreyfus F, Bonnet D, Lacombe C, Mayeux P, Bouscary D, Tamburini J. The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia. Leukemia. 2011 Dec 6. doi: 10.1038/leu.2011.339. [Epub ahead of print] PubMed PMID: 22143671.

4: Huang S, Yang ZJ, Yu C, Sinicrope FA. Inhibition of mTOR kinase by AZD8055 can antagonize chemotherapy-induced cell death through autophagy induction and down-regulation of p62/sequestosome 1. J Biol Chem. 2011 Nov 18;286(46):40002-12. Epub 2011 Sep 23. PubMed PMID: 21949121; PubMed Central PMCID: PMC3220585.

5: Shao H, Gao C, Tang H, Zhang H, Roberts LR, Hylander BL, Repasky EA, Ma WW, Qiu J, Adjei AA, Dy GK, Yu C. Dual targeting of mTORC1/C2 complexes enhances histone deacetylase inhibitor-mediated anti-tumor efficacy in primary HCC cancer in vitro and in vivo. J Hepatol. 2012 Jan;56(1):176-83. Epub 2011 Aug 9. PubMed PMID: 21835141.

6: Shi H, Kong X, Ribas A, Lo RS. Combinatorial treatments that overcome PDGFRβ-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res. 2011 Aug 1;71(15):5067-74. PubMed PMID: 21803746; PubMed Central PMCID: PMC3149831.

7: Jiang Q, Weiss JM, Back T, Chan T, Ortaldo JR, Guichard S, Wiltrout RH. mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment. Cancer Res. 2011 Jun 15;71(12):4074-84. Epub 2011 May 3. PubMed PMID: 21540234; PubMed Central PMCID: PMC3116937.

8: Marshall G, Howard Z, Dry J, Fenton S, Heathcote D, Gray N, Keen H, Logie A, Holt S, Smith P, Guichard SM. Benefits of mTOR kinase targeting in oncology: pre-clinical evidence with AZD8055. Biochem Soc Trans. 2011 Apr;39(2):456-9. Review. PubMed PMID: 21428919.

9: García-Martínez JM, Wullschleger S, Preston G, Guichard S, Fleming S, Alessi DR, Duce SL. Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice. Br J Cancer. 2011 Mar 29;104(7):1116-25. Epub 2011 Mar 15. PubMed PMID: 21407213; PubMed Central PMCID: PMC3068512.

10: Houghton PJ, Gorlick R, Kolb EA, Lock R, Carol H, Morton CL, Keir ST, Reynolds CP, Kang MH, Phelps D, Maris JM, Billups C, Smith MA. Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Feb;58(2):191-9. doi: 10.1002/pbc.22935. Epub 2011 Feb 18. PubMed PMID: 21337679.



Additional Information

AZD8055 is a novel ATP-competitive inhibitor of mTOR kinase activity with an IC50 of 0.8 nmol/L. AZD8055 showed excellent selectivity (~1,000-fold) against all class I phosphatidylinositol 3-kinase (PI3K) isoforms and other members of the PI3K-like kinase family. Furthermore, there was no significant activity against a panel of 260 kinases at concentrations up to 10 μmol/L. AZD8055 inhibits the phosphorylation of mTORC1 substrates p70S6K and 4E-BP1 as well as phosphorylation of the mTORC2 substrate AKT and downstream proteins. The rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1 were fully inhibited by AZD8055, resulting in significant inhibition of cap-dependent translation. In vitro, AZD8055 potently inhibits proliferation and induces autophagy in H838 and A549 cells. In vivo, AZD8055 induces a dose-dependent pharmacodynamic effect on phosphorylated S6 and phosphorylated AKT at plasma concentrations leading to tumor growth inhibition. Notably, AZD8055 results in significant growth inhibition and/or regression in xenografts, representing a broad range of human tumor types. AZD8055 is currently in phase I clinical trials. ( Source: Cancer Res; 70(1); 288-98 ).