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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)

Authors:
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.

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


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.


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