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Optimization of hERG and pharmacokinetic properties for basic dihydro-8H-purin-8-one inhibitors of DNA-PK

DOI: 10.1021/acsmedchemlett.2c00172 DOI Help

Authors: Frederick W. Goldberg (AstraZeneca) , Attilla K. T. Ting (AstraZeneca) , David Beattie (AstraZeneca) , Gillian M. Lamont (AstraZeneca) , Charlene Fallan (AstraZeneca) , M. Raymond V. Finlay (AstraZeneca) , Beth Williamson (AstraZeneca) , Marianne Schimpl (AstraZeneca) , Alexander R. Harmer (AstraZeneca) , Oladipupo B. Adeyemi (AstraZeneca) , Pär Nordell (AstraZeneca) , Anna S. Cronin (AstraZeneca) , Mercedes Vazquez-Chantada (AstraZeneca) , Derek Barratt (AstraZeneca) , Antonio Ramos-Montoya (AstraZeneca) , Elaine B. Cadogan (AstraZeneca) , Barry R. Davies (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters

State: Published (Approved)
Published: July 2022
Diamond Proposal Number(s): 20015

Abstract: The DNA-PK complex is activated by double-strand DNA breaks and regulates the non-homologous end-joining repair pathway; thus, targeting DNA-PK by inhibiting the DNA-PK catalytic subunit (DNA-PKcs) is potentially a useful therapeutic approach for oncology. A previously reported series of neutral DNA-PKcs inhibitors were modified to incorporate a basic group, with the rationale that increasing the volume of distribution while maintaining good metabolic stability should increase the half-life. However, adding a basic group introduced hERG activity, and basic compounds with modest hERG activity (IC50 = 10–15 μM) prolonged QTc (time from the start of the Q wave to the end of the T wave, corrected by heart rate) in an anaesthetized guinea pig cardiovascular model. Further optimization was necessary, including modulation of pKa, to identify compound 18, which combines low hERG activity (IC50 = 75 μM) with excellent kinome selectivity and favorable pharmacokinetic properties.

Journal Keywords: DNA-PK; hERG; pKa; kinase; permeability; volume of distribution; oncology

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

Instruments: I03-Macromolecular Crystallography

Added On: 13/07/2022 10:53

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)