AZD1390
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MedKoo CAT#: 206857

CAS#: 2089288-03-7

Description: 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

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AZD1390
CAS# 2089288-03-7
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 206857
Name: AZD1390
CAS#: 2089288-03-7
Chemical Formula: C27H32FN5O2
Exact Mass: 477.25
Molecular Weight: 477.580
Elemental Analysis: C, 67.90; H, 6.75; F, 3.98; N, 14.66; O, 6.70

Price and Availability

Size Price Availability Quantity
5mg USD 150 Ready to ship
10mg USD 250 Ready to ship
25mg USD 550 Ready to ship
50mg USD 950 Ready to ship
100mg USD 1650 Ready to ship
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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.

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/

Solubility Data

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

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.

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:
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.

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http://mct.aacrjournals.org/content/17/1_Supplement/A124