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The discovery of 7-methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor

DOI: 10.1021/acs.jmedchem.9b01684 DOI Help

Authors: Frederick Woolf Goldberg (AstraZeneca) , M. Raymond V. Finlay (AstraZeneca) , Attilla Ting (AstraZeneca) , David Beattie (AstraZeneca) , Gillian Lamont (AstraZeneca) , Charlene Fallan (AstraZeneca) , Gail Wrigley (AstraZeneca) , Marianne Schimpl (AstraZeneca) , Martin R. Howard (AstraZeneca) , Beth Williamson (AstraZeneca) , Mercedes Vazquez-Chantada (AstraZeneca) , Derek Barratt (AstraZeneca) , Barry Davies (AstraZeneca) , Elaine Cadogan (AstraZeneca) , Antonio Ramos Montoya (AstraZeneca) , Emma Dean (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: December 2019

Abstract: DNA-PK is a key component within the DNA damage response, as it is responsible for recognizing and repairing double-strand DNA breaks (DSBs) via non-homologous end joining. Historically it has been challenging to identify inhibitors of the DNA-PK catalytic subunit (DNA-PKcs) with good selectivity versus the structurally related PI3 (lipid) and PI3K-related protein kinases. We screened our corporate collection for DNA-PKcs inhibitors with good PI3 kinase selectivity, identifying compound 1. Optimization focused on further improving selectivity whilst improving physical and pharmacokinetic properties, notably co-optimization of permeability and metabolic stability, to identify compound 16 (AZD7648). Compound 16 had no significant off-targets in the protein kinome, and only weak activity versus PI3Kα/γ lipid kinases. Monotherapy activity in murine xenograft models was observed, and regressions were observed when combined with inducers of DSBs (doxorubicin or irradiation) or PARP inhibition (olaparib). These data support progression into clinical studies (NCT03907969).

Journal Keywords: DNA-PK; AZD7648; DDR; kinase; permeability; selectivity; PIKK; oncology; cancer; PARP; olaparib

Subject Areas: Chemistry, Medicine, Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography

Added On: 08/01/2020 12:02

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Cancer Drug Discovery Non-Communicable Diseases Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)