Identification of Novel, Selective Ataxia-Telangiectasia Mutated Kinase Inhibitors with the Ability to Penetrate the Blood-Brain Barrier: The Discovery of AZD1390

The inhibition of ataxia-telangiectasia mutated (ATM) has been shown to chemo- and radio-sensitize human glioma cells in vitro and therefore might provide an exciting new paradigm in the treatment of glioblastoma multiforme (GBM). The effective treatment of GBM will likely require a compound with th...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 67; no. 4; pp. 3090 - 3111
Main Authors: Pike, Kurt G., Hunt, Thomas A., Barlaam, Bernard, Benstead, David, Cadogan, Elaine, Chen, Kan, Cook, Calum R., Colclough, Nicola, Deng, Chao, Durant, Stephen T., Eatherton, Andrew, Goldberg, Kristin, Johnstro''m, Peter, Liu, Libin, Liu, Zhaoqun, Nissink, J. Willem M., Pang, Chengling, Pass, Martin, Robb, Graeme R., Roberts, Caroline, Schou, Magnus, Steward, Oliver, Sykes, Andy, Yan, Yumei, Zhai, Baochang, Zheng, Li
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 22.02.2024
Subjects:
Animals
Ataxia Telangiectasia - drug therapy
Ataxia Telangiectasia Mutated Proteins
ATP Binding Cassette Transporter, Subfamily G, Member 2
Blood-Brain Barrier - metabolism
Chemistry, Medicinal
Glioblastoma - drug therapy
Humans
Life Sciences & Biomedicine
Neoplasm Proteins
Pharmacology & Pharmacy
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Pyridines
Quinolones
Science & Technology
POTENT
DESIGN
ALIGNMENT
PROTEIN-KINASE
GLIOMA
ATM
CARBOXAMIDES
MULTIPARAMETER OPTIMIZATION
CANCER
STRATEGIES
ISSN:0022-2623, 1520-4804, 1520-4804
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The inhibition of ataxia-telangiectasia mutated (ATM) has been shown to chemo- and radio-sensitize human glioma cells in vitro and therefore might provide an exciting new paradigm in the treatment of glioblastoma multiforme (GBM). The effective treatment of GBM will likely require a compound with the potential to efficiently cross the blood-brain barrier (BBB). Starting from clinical candidate AZD0156, 4, we investigated the imidazoquinolin-2-one scaffold with the goal of improving likely CNS exposure in humans. Strategies aimed at reducing hydrogen bonding, basicity, and flexibility of the molecule were explored alongside modulating lipophilicity. These studies identified compound 24 (AZD1390) as an exceptionally potent and selective inhibitor of ATM with a good preclinical pharmacokinetic profile. 24 showed an absence of human transporter efflux in MDCKII-MDR1-BCRP studies (efflux ratio <2), significant BBB penetrance in nonhuman primate PET studies (K-p,K-uu 0.33) and was deemed suitable for development as a clinical candidate to explore the radiosensitizing effects of ATM in intracranial malignancies.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.3c02277