Home PI3K/Akt/mTOR ATM/ATR inhibitor AZD1390

AZD1390

Catalog No.S8680

For research use only.

AZD1390 is a first-in-class orally available and CNS penetrant ATM inhibitor with an IC50 of 0.78 nM in cells and >10,000-fold selectivity over closely related members of the PIKK family of enzymes and excellent selectivity across a broad panel of kinases.

AZD1390 Chemical Structure

CAS No. 2089288-03-7

Selleck's AZD1390 has been cited by 11 Publications

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Biological Activity

Description AZD1390 is a first-in-class orally available and CNS penetrant ATM inhibitor with an IC50 of 0.78 nM in cells and >10,000-fold selectivity over closely related members of the PIKK family of enzymes and excellent selectivity across a broad panel of kinases.
Targets
ATM [1]
(Cell-based assay)
0.78 nM
In vitro

AZD1390 blocks ATM-dependent DDR (DNA damage response) pathway activity and combines with radiation to induce G2 cell cycle phase accumulation, micronuclei, and apoptosis. AZD1390 radiosensitizes glioma and lung cancer cell lines, with p53 mutant glioma cells generally being more radiosensitized than wild type. AZD1390 results in increased genome instability[2].
Assay
Methods Test Index PMID
Western blot pATM (S1981) / ATM / pKAP1(S824) / KAP1 / pCDK1 ; pChk2 29938225
In vivo AZD1390 displays excellent oral bioavailability in preclinical species (66% in rat and 74% in dog). It can efficiently cross the BBB in non-human primate PET studies. Profound tumor regressions and increased animal survival (>50 days) have been observed in orthotopic xenograft models of brain cancer following just 2 or 4 days combination treatment of AZD1390 with radiotherapy, compared to radiotherapy treatment alone[1]. In in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models, AZD1390 dosed in combination with daily fractions of IR (whole-brain or stereotactic radiotherapy) significantly induces tumor regressions and increased animal survival compared to IR treatment alone. AZD1390 has favorable physical, chemical, PK, and PD properties suitable for clinical applications that require exposures within the central nervous system[2].

Protocol (from reference)

Cell Research:

[2]
  • Cell lines: NCI-H2228 cells
  • Concentrations: 0-1250 nM
  • Incubation Time: 1 h
  • Method:

    Cells (3000 per well) are seeded in a 384-well format in RPMI with 10% fetal bovine serum.After 24 hours, plates are Echo-dosed with a semi-log dose dilution of each compound from a top concentration of 1250 nM. One hour after compound dosing, plates are irradiated with 0, 2.5, or 4 Gy. At 1, 6, 24, and 48 hours after irradiation, plates are fixed by adding a 1:1 volume of 8% PFA directly to the medium to give a final concentration of 4% PFA and incubated for 30 min at room temperature before washing three times with phosphate-buffered saline solution (PBSA).
Animal Research:

[2]
  • Animal Models: a lung NCI-H2228 xenograftmodel either implanted into nude mice brains directly (intracranial brain) or injected into the carotid artery [intracarotid artery (ICA)]
  • Dosages: 5, 15 and 20 mg/kg
  • Administration: by oral gavage

Solubility (25°C)

In vitro

 Ethanol 95 mg/mL
(198.92 mM)
DMSO 14 mg/mL
(29.31 mM)
Water Insoluble

Chemical Information

Molecular Weight 477.57
Formula

C27H32FN5O2
CAS No. 2089288-03-7
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC(C)N1C2=C(C=NC3=CC(=C(C=C32)C4=CN=C(C=C4)OCCCN5CCCCC5)F)N(C1=O)C

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

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT05182905 Not yet recruiting Drug: AZD1390 Glioblastoma|Glioma|Glioblastoma Multiforme|Glioma Malignant Nader Sanai|Barrow Neurological Institute|Ivy Brain Tumor Center|AstraZeneca|St. Joseph''s Hospital and Medical Center Phoenix January 2022 Early Phase 1
NCT03423628 Recruiting Radiation: Radiation Therapy|Drug: AZD1390 Recurrent Glioblastoma Multiforme|Primary Glioblastoma Multiforme|Brain Neoplasms Malignant|Leptomeningeal Disease (LMD) AstraZeneca April 2 2018 Phase 1
NCT03215381 Completed Drug: [11C]AZD1390 Healthy Volunteer Male Subjects AstraZeneca|Karolinska Institutet Quintiles IMS October 10 2017 Phase 1

(data from https://clinicaltrials.gov, updated on 2022-01-17)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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