Undisclosed Ku-DNA binding inhibitor / NERx Biosci - LARVOL DELTA

Design, synthesis, and structure-activity relationship studies of 4-substituted phenylpyrazolidinone derivatives as potent Ku70/80 targeted DNA-PK inhibitors. (PubMed, RSC Med Chem) - "The thermal stability analysis also supports the notion that these Ku-DBi's bind to the Ku as measured by nanoDSF (Differential Scanning Fluorimetry), which is consistent with the observed SAR trends. These Ku-DBi's may serve as candidate compounds for further modification and development as anticancer therapeutics in combination with radiotherapy or DSB-inducing agents to treat certain DNA repair-deficient cancers."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Optimized Ku-DNA binding inhibitors impact the cellular and in vivo DNA damage response to DSB-inducing therapies (EORTC-NCI-AACR 2024) - "These data demonstrate that small molecules drugs targeting Ku-DNA interaction inhibit DNA-PK, the DDR and NHEJ pathways, resulting in sensitization of cancer cells to DNA-damaging anti-cancer agents. These data of the first in vivo studies of Ku-DBi activity represent a significant advance in the development of Ku-DNA binding targeted therapeutics for cancer treatment."

Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Impact of Optimized Ku-DNA Binding Inhibitors on the Cellular and In Vivo DNA Damage Response. (PubMed, Cancers (Basel)) - "In vivo studies in an NSCLC xenograft model demonstrated that the Ku-DBi treatment blocked IR-dependent DNA-PKcs autophosphorylation, modulated DDR, and reduced tumor cell proliferation. This represents the first in vivo demonstration of a Ku-targeted DNA-binding inhibitor impacting IR response and highlights the potential therapeutic utility of Ku-DBis for cancer treatment."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRCA1

Ku-DNA binding inhibitors modulate the DNA damage response in response to DNA double-strand breaks. (PubMed, NAR Cancer) - "In this study, we demonstrate that chemical inhibition of the Ku-DNA interaction potentiates the cellular effects of bleomycin and IR via p53 phosphorylation through the activation of the ATM pathway. This response is concomitant with a reduction of DNA-PK catalytic subunit (DNA-PKcs) autophosphorylation at S2056 and a time-dependent increase in H2AX phosphorylation at S139. These results are consistent with Ku-DBi's abrogating DNA-PKcs autophosphorylation to impact DSB repair and DDR signaling through a novel mechanism of action, and thus represent a promising anticancer therapeutic strategy in combination with DNA DSB-inducing agents."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Ku-DNA binding inhibitors modulate the DNA damage response in response to DNA double-strand breaks (AACR-NCI-EORTC 2022) - "Ku-DBis display nanomolar activity in vitro, possess cellular DNA-PK and NHEJ inhibitory activity, and sensitize non-small cell lung cancer (NSCLC) cells to DSB generating chemotherapeutics bleomycin and etoposide. These data are consistent with Ku-DBis possessing a novel mechanism of action that abrogates autophosphorylation of DNA-PKcs to impact DSB repair and potentially DDR signaling, becoming in a promising approach as part of an anticancer therapeutic strategy in combination with DNA DSBs-inducing agents. No"

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor