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2022 - Optimization of hERG and Pharmacokinetic Properties for Basic Dihydro-8H-purin-8-one Inhibitors of DNA-PK

icon sp96 SyncroPatch 384PE (a predecessor model of the SyncroPatch 384 instrument) publication in ACS Medicinal Chemistry Letters (2022)

Goldberg F.W., Ting A.K.T., Beattie D., Lamont G.M., Fallan C., Finlay M.R.V., Williamson B., Schimpl M., Harmer A.R., Adeyemi O.B., Nordell P., Cronin A.S., Vazquez-Chantada M., Barratt D., Ramos-Montoya A., Cadogan E.B., Davies B.R.

ACS Medicinal Chemistry Letters (2022) doi:10.1021/acsmedchemlett.2c00172   


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.

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