Design, synthesis, and structure-activity relationship studies of 4-substituted phenylpyrazolidinone derivatives as potent Ku70/80 targeted DNA-PK inhibitors.

ABSTRACT: The Ku70-Ku80 (Ku) heterodimer complex plays a central role in the non-homologous end joining (NHEJ) double-strand break (DSB) repair pathway and the DNA damage response (DDR). Like DNA-PK, Ku is a promising drug target for cancer treatment when combined with radiotherapy or DSB-inducing agents. We have previously reported the first-in-class, early-generation, highly potent, and specific Ku-DNA binding inhibitors (Ku-DBi's) that block the Ku interaction with DNA and inhibit DNA-PK kinase activity. These early-generation Ku-DBi's also inhibit cellular DNA-PK, NHEJ-catalyzed DSB repair, sensitize non-small cell lung cancer (NSCLC) cells to DSB-inducing agents, and potentiate the cellular effects of these agents via p53 phosphorylation through the activation of the ATM pathway. In this

SUBMITTER: Kushwaha ND 

PROVIDER: S-EPMC12452633 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature