AZD1390 | CAS#2089288-03-7 | ATM inhibitor

MedKoo Cat#: 206857 | Name: AZD1390

Description:

WARNING: This product is for research use only, not for human or veterinary use.

AZD1390 is a potent and selective ATM inhibitor with the ability to cross the blood-brain barrier suitable for the treatment of intracranial malignancies.AZD1390 is an exceptionally potent inhibitor of ATM in cells (IC50 = 0.78 nM) with >10,000-fold selectivity over closely related members of the PIKK family of enzymes and excellent selectivity across a broad panel of kinases. AZD1390 displays excellent oral bioavailability in preclinical species (66% in rat and 74% in dog), is not a substrate for human efflux transporters, and has been shown to efficiently cross the BBB in non-human primate PET studies.

Chemical Structure

AZD1390

CAS#2089288-03-7

Theoretical Analysis

MedKoo Cat#: 206857

Name: AZD1390

CAS#: 2089288-03-7

Chemical Formula: C27H32FN5O2

Exact Mass: 477.2540

Molecular Weight: 477.58

Elemental Analysis: C, 67.90; H, 6.75; F, 3.98; N, 14.66; O, 6.70

Price and Availability

Size	Price	Availability
5mg	USD 150.00	Ready to ship
10mg	USD 250.00	Ready to ship
25mg	USD 550.00	Ready to ship
50mg	USD 950.00	Ready to ship
100mg	USD 1,650.00	Ready to ship

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Related CAS #

No Data

Synonym

AZD1390; AZD-1390; AZD 1390;

IUPAC/Chemical Name

7-fluoro-1-isopropyl-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-2(3H)-one

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

SMILES Code

O=C(N1C(C)C)N(C)C2=C1C3=CC(C4=CC=C(OCCCN5CCCCC5)N=C4)=C(F)C=C3N=C2

Appearance

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

Shelf Life

>2 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

More Info

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. These data support the potential of CNS-penetrant ATM inhibitors to provide an important new therapeutic agent for the treatment of intracranial malignancies. AZD1390 is currently undergoing early clinical assessment. References: (1) Stupp R, Hegi ME, Gilbert MR, Chakravarti A. Chemoradiotherapy in malignant glioma: standard of care and future directions, J Clin Oncol 2007;25:4127-36. (2) Ajaz M, Jefferies S, Brazil L, Watts C, Chalmers A. Current and investigational drug strategies for glioblastoma. Clin Oncol 2014;26:419-30.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A22T07K07

QC Data

View QC data: current batch, Lot#A22T07K07

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

AZD1390 is a potent, highly selective, orally bioavailable, brain-penetrant ATM inhibitor with an IC50 of 0.78 nM in cell.

In vitro activity:

In cell activity screens, AZD1390 caused inhibition of ATM, as indicated by the inhibition of phosphorylation of ATMSer1981 in HT29 cells (used historically and routinely as a consistent cell assay for other projects and selectivity studies) following treatment with irradiation. The reported IC50 values were calculated as the geometric mean of IC50 individual values and the arithmetic mean of pIC50 values. The cellular effects of AZD1390 on the ATM-dependent DDR was investigated. Figure 2 (A and B) illustrates that ATM autophosphorylation inhibition by AZD1390 occurred at 4 hours after treatment, and 3 nM produced a strong inhibition of ATM in LN18 GBM cells (other time points were investigated in fig. S1, A to C). Other DDR inhibitors tested under the same conditions at relevant IC50 concentrations did not affect pATM levels. After removing AZD1390 and allowing cells to recover, evidence for ATM pathway reactivation was observed at 6 hours as pChk2 levels started to rise (Fig. 2B). To confirm selectivity observed in our cell screens, effects on DNA-PK and ATR pathway activation were checked and appreciable effects in Western blots were not seen (fig. S1, B and C). Figure 2C shows the effects of AZD1390 added 1 hour before irradiation to NCI-H2228 lung cancer cells (used in subsequent orthotopic brain metastatic in vivo model) in high-content immunofluorescence cell imaging (using the confocal CV7000 imaging microscope) analyzing pATM and γH2AX DDR biomarkers. The median 50% excitatory concentration (XC50) values for AZD1390 using total nuclear staining of pATM and γH2AX are in general agreement with the pATM assay potencies (0.78 nM) reported in the HT29 cell screen (Table 1 and fig. S2A). However, XC50 concentrations required to inhibit discreet nuclear pATM foci were higher (2.7 nM) and in agreement with the Western blot data and antiproliferation effects (seen in subsequent results). The data also show that radiation combined with AZD1390 dose-dependently increased the formation of micronuclei—DNA-containing structures indicative of incompletely replicated or broken chromosome fragments. This suggest that AZD1390 results in increased genome instability. Reference: Sci Adv. 2018 Jun 20;4(6):eaat1719. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/29938225/

In vivo activity:

A series of efficacy studies were performed using a lung NCI-H2228 xenograft model either implanted into nude mice brains directly (intracranial brain) or injected into the carotid artery [intracarotid artery (ICA)] and allowed to establish in the brain. Figure 4A shows data that demonstrate a dose-dependent tumor growth inhibition (TGI), with marginal inhibition observed using AZD1390 (5 mg/kg) dosed an hour before each daily fraction of IR. Superior efficacy was observed dosing at 20 mg/kg once daily (QD) or twice daily (BID) in combination with the four daily fractions of IR. The data show the survival of the same mice. Figure S5 (A and B) shows a repeat experiment using BID dosing. Reference: Sci Adv. 2018 Jun 20;4(6):eaat1719. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/29938225/

	Solvent	mg/mL	mM
Solubility
	DMSO	10.0	20.93
	Ethanol	80.0	168.51

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 477.58 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.

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:

In vitro protocol:

1. Durant ST, Zheng L, Wang Y, Chen K, Zhang L, Zhang T, Yang Z, Riches L, Trinidad AG, Fok JHL, Hunt T, Pike KG, Wilson J, Smith A, Colclough N, Reddy VP, Sykes A, Janefeldt A, Johnström P, Varnäs K, Takano A, Ling S, Orme J, Stott J, Roberts C, Barrett I, Jones G, Roudier M, Pierce A, Allen J, Kahn J, Sule A, Karlin J, Cronin A, Chapman M, Valerie K, Illingworth R, Pass M. The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Sci Adv. 2018 Jun 20;4(6):eaat1719. doi: 10.1126/sciadv.aat1719. PMID: 29938225; PMCID: PMC6010333.

In vivo protocol:

1: Durant ST, Zheng L, Wang Y, Chen K, Zhang L, Zhang T, Yang Z, Riches L, Trinidad AG, Fok JHL, Hunt T, Pike KG, Wilson J, Smith A, Colclough N, Reddy VP, Sykes A, Janefeldt A, Johnström P, Varnäs K, Takano A, Ling S, Orme J, Stott J, Roberts C, Barrett I, Jones G, Roudier M, Pierce A, Allen J, Kahn J, Sule A, Karlin J, Cronin A, Chapman M, Valerie K, Illingworth R, Pass M. The brain- penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Sci Adv. 2018 Jun 20;4(6):eaat1719. doi: 10.1126/sciadv.aat1719. PMID: 29938225; PMCID: PMC6010333. 2: Tew BY, Kalfa AJ, Yang Z, Hurth KM, Simon T, Abnoosian E, Durant ST, Hamerlik P, Salhia B. ATM-Inhibitor AZD1390 Is a Radiosensitizer for Breast Cancer CNS Metastasis. Clin Cancer Res. 2023 Nov 1;29(21):4492-4503. doi: 10.1158/1078-0432.CCR-23-0290. PMID: 37585496; PMCID: PMC10618650. 3: Jin MH, Oh DY. ATM in DNA repair in cancer. Pharmacol Ther. 2019 Nov;203:107391. doi: 10.1016/j.pharmthera.2019.07.002. Epub 2019 Jul 9. PMID: 31299316. 4: Lan Z, Qu LJ, Liang Y, Chen LQ, Xu S, Ge JW, Xue ZW, Bao XY, Xia SN, Yang HY, Huang J, Xu Y, Zhu XL. AZD1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia-mediated neuroinflammation and ischemic brain injury. CNS Neurosci Ther. 2024 Apr;30(4):e14696. doi: 10.1111/cns.14696. PMID: 38668740; PMCID: PMC11048048. 5: Chen J, Laverty DJ, Talele S, Bale A, Carlson BL, Porath KA, Bakken KK, Burgenske DM, Decker PA, Vaubel RA, Eckel-Passow JE, Bhargava R, Lou Z, Hamerlik P, Harley B, Elmquist WF, Nagel ZD, Gupta SK, Sarkaria JN. Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization. Sci Transl Med. 2024 Feb 14;16(734):eadj5962. doi: 10.1126/scitranslmed.adj5962. Epub 2024 Feb 14. PMID: 38354228; PMCID: PMC11064970. 6: Laverty DJ, Gupta SK, Bradshaw GA, Hunter AS, Carlson BL, Calmo NM, Chen J, Tian S, Sarkaria JN, Nagel ZD. ATM inhibition exploits checkpoint defects and ATM-dependent double strand break repair in TP53-mutant glioblastoma. Nat Commun. 2024 Jun 21;15(1):5294. doi: 10.1038/s41467-024-49316-8. PMID: 38906885; PMCID: PMC11192742. 7: Jucaite A, Stenkrona P, Cselényi Z, De Vita S, Buil-Bruna N, Varnäs K, Savage A, Varrone A, Johnström P, Schou M, Davison C, Sykes A, Pilla Reddy V, Hoch M, Vazquez-Romero A, Moein MM, Halldin C, Merchant MS, Pass M, Farde L. Brain exposure of the ATM inhibitor AZD1390 in humans-a positron emission tomography study. Neuro Oncol. 2021 Apr 12;23(4):687-696. doi: 10.1093/neuonc/noaa238. PMID: 33123736; PMCID: PMC8041329. 8: Özdemir D, Ağca CA. AZD1390, an Ataxia telangiectasia mutated inhibitor, enhances cisplatin mediated apoptosis in breast cancer cells. Exp Cell Res. 2025 Jan 15;444(2):114382. doi: 10.1016/j.yexcr.2024.114382. Epub 2024 Dec 15. PMID: 39681282. 9: Xie J, Kuriakose T, Bianski B, Twarog N, Savage E, Xu K, Zhu X, He C, Hansen B, Wang H, High A, Li Y, Rehg JE, Tillman HS, Freeman BB, Rankovic Z, Onar- Thomas A, Fan Y, Wu G, Peng J, Miller S, Baker SJ, Shelat AA, Tinkle CL. ATM inhibition enhances the efficacy of radiation across distinct molecular subgroups of pediatric high-grade glioma. Neuro Oncol. 2023 Oct 3;25(10):1828-1841. doi: 10.1093/neuonc/noad064. PMID: 36971093; PMCID: PMC10547515. 10: Ahmed Z, Tuxworth RI. The brain-penetrant ATM inhibitor, AZD1390, promotes axon regeneration and functional recovery in preclinical models of spinal cord injury. Clin Transl Med. 2022 Jul;12(7):e962. doi: 10.1002/ctm2.962. PMID: 35818848; PMCID: PMC9274214.