AZD1390

Alias: AZD-1390; AZD1390; AZD 1390
Cat No.:V0075 Purity: ≥98%
AZD1390 (AZD-1390) is a novel, potent, selective, first-in-class orally bioavailable and CNS penetrant inhibitor of Ataxia-telangiectasia mutated (ATM) kinase with potential anticancer activity.
AZD1390 Chemical Structure CAS No.: 2089288-03-7
Product category: ATM(ATR)
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

AZD1390 (AZD-1390) is a novel, potent, selective, first-in-class orally bioavailable and CNS penetrant inhibitor of Ataxia-telangiectasia mutated (ATM) kinase with potential anticancer activity. In cell assays, it inhibits ATM with an IC50 of 0.78 nM. It exhibits excellent selectivity across a wide range of kinases and is >10,000 fold more selective than the closely related PIKK family of enzymes. Treating intracranial malignancies is appropriate for AZD1390 because it can cross the blood-brain barrier (BBB). Both lung cancer and glioma cell lines are radiosensitized by AZD1390; p53 mutant glioma cells are typically more radiosensitized than wild type. As a radiosensitizer for tumors of the central nervous system, AZD1390 is currently in the early stages of clinical research.

Biological Activity I Assay Protocols (From Reference)
Targets
ATM ( IC50 = 0.78 nM )
ln Vitro

AZD1390 inhibits the activity of the ATM-dependent DDR (DNA damage response) pathway, causing micronuclei, apoptosis, and accumulation of the G2 cell cycle phase in conjunction with radiation. Glioma and lung cancer cell lines are radiosensitized to AZD1390; p53 mutant glioma cells are typically more radiosensitized than wild type. AZD1390 increases the instability of the genome[2].

ln Vivo
AZD1390 exhibits superior oral bioavailability in preclinical species (64 percent in rats and 74 percent in dogs). PET studies on non-human primates have shown that it can effectively cross the blood-brain barrier. When AZD1390 is combined with radiation therapy for just two or four days, as opposed to radiotherapy alone, profound tumor regressions and longer animal survival (>50 days) have been seen in orthotopic xenograft models of brain cancer[1]. AZD1390 dosed in conjunction with daily fractions of IR (whole-brain or stereotactic radiotherapy) significantly induces tumor regressions and increased animal survival compared to IR treatment alone in in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models. For clinical applications requiring exposures inside the central nervous system, AZD1390 offers advantageous physical, chemical, PK, and PD properties[2].
Cell Assay
In an RPMI format, 3000 cells per well are seeded using 10% fetal bovine serum in a 384-well format.Plates are Echo-dosed with a semi-log dose dilution of each compound after a 24-hour period, starting at a top concentration of 1250 nM. After compound dosing, plates are exposed to 0, 2.5, or 4 Gy of radiation for one hour. After the plates are fixed at 1, 6, 24, and 48 hours after the radiation, they are incubated for 30 minutes at room temperature and then three times with phosphate-buffered saline solution (PBSA). This is done by directly adding a 1:1 volume of 8% PFA to the medium, resulting in a final concentration of 4% PFA.
Animal Protocol
Bioluminescent imaging (BLI) is performed after intracranial implantation of mouse GL261 glioma (p53 mutant) cells into immunocompetent, syngeneic C57/bl6 mice, before the mice are randomly assigned. Before receiving several fractions of 2-3 Gy of radiation over the course of two to four days, AZD1390 is given orally via gavage. Radiation therapy is applied to the tumor site using a 5 x 5 mm lateral field using the Small Animal Radiation Research Platform (SARRP).
References

[1]. AACR Mol Cancer Ther. 2018, 17(1 Suppl):Abstract nr A124.

[2]. Science Advances. 2018, 4(6): eaat1719.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C27H32FN5O2
Molecular Weight
477.57
Exact Mass
477.25
Elemental Analysis
C, 67.90; H, 6.75; F, 3.98; N, 14.66; O, 6.70
CAS #
2089288-03-7
Appearance
Solid powder
SMILES
CC(C)N1C2=C(C=NC3=CC(=C(C=C32)C4=CN=C(C=C4)OCCCN5CCCCC5)F)N(C1=O)C
InChi Key
VQSZIPCGAGVRRP-UHFFFAOYSA-N
InChi Code
InChI=1S/C27H32FN5O2/c1-18(2)33-26-21-14-20(22(28)15-23(21)29-17-24(26)31(3)27(33)34)19-8-9-25(30-16-19)35-13-7-12-32-10-5-4-6-11-32/h8-9,14-18H,4-7,10-13H2,1-3H3
Chemical Name
7-fluoro-3-methyl-8-[6-(3-piperidin-1-ylpropoxy)pyridin-3-yl]-1-propan-2-ylimidazo[4,5-c]quinolin-2-one
Synonyms
AZD-1390; AZD1390; AZD 1390
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: > 10mM
Water: N/A
Ethanol: N/A
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.0939 mL 10.4697 mL 20.9393 mL
5 mM 0.4188 mL 2.0939 mL 4.1879 mL
10 mM 0.2094 mL 1.0470 mL 2.0939 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04550104 Recruiting Drug: AZD1390
Drug: TBD Compound 1
Non Small Cell Lung Cancer University of Leeds March 17, 2021 Phase 1
NCT05116254 Recruiting Combination Product: AZD1390 +
radiotherapy
Soft Tissue Sarcoma Adult The Netherlands Cancer Institute July 18, 2022 Phase 1
NCT05678010 Recruiting Radiation: Stereotactic Body
Radiotherapy
Drug: AZD1390
Solid Tumor
Solid Carcinoma
Memorial Sloan Kettering Cancer
Center
May 17, 2023 Phase 1
NCT03423628 Recruiting Radiation: Radiation Therapy
Drug: AZD1390
Brain Neoplasms, Malignant
Leptomeningeal Disease
(LMD)
AstraZeneca April 2, 2018 Phase 1
NCT05182905 Recruiting Drug: AZD1390 Glioblastoma
Glioma
Nader Sanai March 9, 2022 Early Phase 1
Biological Data
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