AI Article Synopsis
- * Researchers modified previously established DNA-PKcs inhibitors by adding a basic group to improve distribution and metabolic stability, but this tweak also caused hERG activity, which can lead to heart issues.
- * Further optimization was needed, resulting in a compound that has low hERG activity and maintains good selectivity and pharmacokinetics for potential therapeutic use.
Article 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 (IC = 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 p , to identify compound , which combines low hERG activity (IC = 75 μM) with excellent kinome selectivity and favorable pharmacokinetic properties.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377022 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.2c00172 | DOI Listing |
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