Discovery of the DNA-PKcs inhibitor DA-143 which exhibits enhanced solubility relative to NU7441.

ABSTRACT: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a vital role in DNA damage repair and lymphocyte function, presenting a significant target in cancer and immune diseases. Current DNA-PKcs inhibitors are undergoing Phase I/II trials as adjuncts to radiotherapy and chemotherapy in cancer. Nevertheless, clinical utility is limited by suboptimal bioavailability. This study introduces DNA-PKcs inhibitors designed to enhance bioavailability. We demonstrate that a novel DNA-PKcs inhibitor, DA-143, surpasses NU7441 in aqueous solubility as well as other available inhibitors. In addition, DA-143 displayed an improvement in DNA-PKcs inhibition relative to NU7441 achieving an IC₅₀ of 2.5 nM. Consistent with current inhibitors, inhibition of DNA-PKcs by DA-143 resulted in inc

SUBMITTER: Waldrip ZJ 

PROVIDER: S-EPMC11358143 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature