NU7441 / AstraZeneca - LARVOL DELTA

Atractylenolide I activates the DNA damage-apoptosis axis in colorectal cancer patient-derived organoids by dual-targeting XRCC5 and CLTC. (PubMed, Phytomedicine) - "This study identifies ATT-1 as a promising multi-targeted therapeutic for colorectal cancer by leveraging PDOs for direct, de novo target discovery. We uniquely identified two novel, high-affinity targets, CLTC and XRCC5, and elucidated a convergent dual-targeting mechanism wherein ATT-1 binding disrupts DNA damage repair and triggers apoptosis. This novel mechanism and its potent synergy with standard chemotherapy in physiologically relevant models provide a compelling strategy for integrating traditional Chinese medicine into modern precision oncology."

Journal • Colorectal Cancer • Metabolic Disorders • Oncology • Solid Tumor • CLTC • XRCC5

Cisplatin-mediated activation of NF-κB promotes lung cancer stem cell formation via DNA repair pathways. (PubMed, J Transl Med) - "This study revealed that NSCLC cells acquire stemness traits through NF-κB activation, with p-DNA-PKcs-induced phosphorylation of p65 being a prerequisite for p65 acetylation and sustained NF-κB activation in drug-resistant cells. Targeting DNA-PKcs represents a novel and effective treatment strategy to overcome DDP resistance in NSCLC."

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

LMNA-PRKDC axis enhances DNA repair and promotes chemoresistance in glioblastoma. (PubMed, Cell Death Dis) - "Glioblastoma (GBM) remains one of the deadliest primary brain tumors, with rapid recurrence and near-universal resistance to temozolomide (TMZ) limiting long-term survival...Inhibition of PRKDC with the ATP-competitive inhibitor KU57788 reversed resistance, restoring TMZ sensitivity and impairing tumor growth in vivo...These results establish the LMNA-PRKDC axis as a functional driver of TMZ resistance through enhanced DNA repair capacity in stem-like tumor subpopulations. Our findings support pharmacologic inhibition of PRKDC as a rational strategy to resensitize resistant GBM to standard chemotherapy and offer a foundation for future biomarker-driven clinical trials targeting DNA repair vulnerabilities in recurrent disease."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • LMNA • PRKDC

Disruption of DNA-PK-Mediated Cgas Retention on Damaged Chromatin Potentiates Doxorubicin-Induced Cgas/Sting-Dependent Anti-Multiple Myeloma Activity (ASH 2023) - "In addition to inducing intrinsic apoptosis of MMCs, activation of cGAS-STING signaling by NU7441/doxorubicin in MMCs also induced M1 polarization of macrophages (Mφs), which increased M1 marker CD86 of Mφs but decreased M2 marker CD163 and CD206, and reduced the IL-10 concentration secreted by Mφs, thus suppressing tumor-protecting potential of M2-like Mφs and improving bortezomib-induced apoptosis of MMCs. Taken together, our study suggests that DNA-PKcs may help maintain the cGAS sequestration in damaged chromatin. Inhibition of DNA-PKcs may consequently disrupt this sequestration, inducing activation of cGAS-STING signaling and improving the efficacy of doxorubicin in treating MM."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • Plasmacytoma • BCL2 • CD163 • CD86 • IL10 • MRC1 • XRCC4

Programmed-Cell-Death-Related Signature Reveals Immune Microenvironment Characteristics and Predicts Therapeutic Response in Diffuse Large B Cell Lymphoma. (PubMed, Biomedicines) - "Drug sensitivity analysis revealed that high-PCDS patients may benefit more from agents like sorafenib and fulvestrant, while low-PCDS patients responded better to NU7441. Notably, the PCDS is closely associated with key immunological characteristics of the TME. These findings advance personalized treatment strategies and support clinically relevant decision-making in DLBCL."

IO biomarker • Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD8 • CTH • PD-1 • PD-L1

Targeting Ku-independent RBMX: A novel strategy to overcome imatinib resistance in chronic myeloid leukemia (ESMO 2025) - "The combination of RBMX depletion with DNA-PK inhibitor NU7441 produced synergistic effects, dramatically enhancing imatinib sensitivity in TKI-resistant cells. Our results suggest that pharmacological targeting of RBMX could represent a promising strategy to overcome TKI resistance and improve treatment outcomes for CML patients. Legal entity responsible for the study The author."

Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • BCR • BRCA2 • RBMX • STC2

Identification and external validation of a prognostic signature based on myeloid-derived suppressor cells-related LncRNAs to evaluate survival prognosis and treatment efficacy in invasive breast carcinoma. (PubMed, Biochem Biophys Rep) - "Among 47 drugs with notable IC50 variations, Ribociclib, PD173074, KU-55933, NU7441, and nutlin-3a exhibited lower IC50 values within the low-risk group, whereas Lapatinib demonstrated greater efficacy among the high-risk group. RT-qPCR validation confirmed the robustness of the model. We successfully verified a new model of molecular markers of MDSCs-related lncRNAs, offering critical insights for predicting outcomes and guiding therapeutic decisions in BRCA cases."

IO biomarker • Journal • Tumor mutational burden • Breast Cancer • Oncology • Solid Tumor • BRCA • TMB

TRP-related gene signatures predict survival and the immune microenvironment in rectal cancer: a comprehensive bioinformatics study. (PubMed, Front Immunol) - "Furthermore, several targeted drugs, including MK-2206, pazopanib, JNK inhibitor VIII, PLX4720, and NU-7441, were associated with risk scores. This study identified five TRP-related biomarkers associated with RC prognosis, providing novel insights into the role of TRP channels in RC development. These findings may contribute to a deeper understanding of RC pathogenesis and offer potential targets for personalized therapy."

Biomarker • Gene Signature • Journal • Colorectal Cancer • Oncology • Rectal Cancer • Solid Tumor • CD8 • GLTP

DDR kinase inhibition causes hypersensitivity to Taxol through caspase-3 activation. (PubMed, Biochem Biophys Res Commun) - "Pharmacological inhibitors, KU55933 (ATM), NU7441 (DNA-PK), and VE821 (ATR), also sensitized V79, CHO, and U2OS human cancer cells to Taxol. These findings suggest that ATM, ATR, and DNA-PK not only facilitate DNA repair but also suppress Taxol-induced apoptosis via caspase-3. Their inhibition may represent a promising strategy to boost their efficacy of Taxol and potentially enhance responses to radiation therapy through combined targeting of mitotic stress and DDR pathways."

Journal • Immunology • Oncology • CASP3 • CASP7

COL10A1+ fibroblasts promote colorectal cancer metastasis and M2 macrophage polarization with pan-cancer relevance. (PubMed, J Exp Clin Cancer Res) - "Our study identifies a CAF subpopulation, COL10A1+Fib, associated with CRC progression and immune suppression, suggesting it as a potential therapeutic target in CRC and possibly other malignancies."

Journal • Pan tumor • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CAFs • ITGB2 • JAK1 • RUNX2 • TGFB1

DNA-PKcs participates in the repair of renal tubular epithelial cell injury. (PubMed, Ren Fail) - "In the hypoxia/reoxygenation (H/R) model using NRK-52E cells, treatment with the DNA-PKcs inhibitor NU7441 resulted in mitochondrial swelling...Moreover, DNA-PKcs inhibition significantly impaired cell proliferation, induced a G1/S phase arrest under normoxic conditions, and resulted in G2/M phase arrest following H/R. Our study provides that DNA-PKcs acts as a promising therapeutic target for mitigating AKI and promoting renal regeneration."

Journal • Acute Kidney Injury • Cardiovascular • Metabolic Disorders • Nephrology • Renal Disease • Reperfusion Injury • VIM

Molecular Insights into Chemotherapy Resistance Mediated by MLL-AF9 Fusion Gene in Pediatric B-Cell Acute Lymphoblastic Leukemia. (PubMed, J Biol Chem) - "In vitro experiments demonstrated that MLL-AF9-overexpressing B-ALL cells exhibited reduced sensitivity to doxorubicin (DOX), cyclophosphamide (CTX), and cisplatin (DDP). Chemoresistance was effectively reversed by the ABC transporter inhibitor Verapamil and the NHEJ inhibitor NU7441 in in vitro and in vivo models. These findings highlight MLL-AF9's role in mediating chemoresistance via ABCB1 and the NHEJ pathways, offering potential therapeutic targets for MLL-AF9-positive B-ALL."

Journal • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • ABCB1 • IGFBP7

Lipopolysaccharide-induced DNA damage response activates DNA-PKcs to drive actin cytoskeleton disruption and cardiac microvascular dysfunction in endotoxemia. (PubMed, Theranostics) - "Inhibition of DNA-PKcs with NU7441 markedly attenuated all these LPS-induced pathologies, improving cardiac function, preserving microvascular structure, preventing mitochondrial fragmentation, and normalizing related gene expression and actin cytoskeleton stability... Our findings suggest that LPS triggers a DNA-PKcs-dependent DDR that promotes mitochondrial fragmentation and actin disruption, particularly in cardiac ECs, contributing to sepsis-induced cardiomyopathy. Targeting DNA-PKcs or mitochondrial fission may hold therapeutic potential for the treatment of sepsis-induced cardiomyopathy."

Journal • Cardiomyopathy • Cardiovascular • Infectious Disease • Septic Shock

Deciphering Nicotine-Driven Oncogenesis in Head and Neck Cancer: Integrative Transcriptomics and Drug Repurposing Insights. (PubMed, Cancers (Basel)) - "Drug repurposing identified five compounds-AZD1332, JAK-8517, NU7441, BRD-K30748066, and neopeltolide-with the first two exhibiting the strongest inverse correlations with nicotine-induced oncogenes in heavy smokers, highlighting their potential as targeted therapies for tobacco-associated HNC. This study comprehensively characterizes nicotine-driven molecular dysregulation in HNC and proposes AZD1332 and JAK-8517 as promising therapeutic candidates through drug repurposing. These insights advance our understanding of nicotine's oncogenic role and provide a foundation for translational research to develop targeted interventions for tobacco-associated HNC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor

Nuclear damage-induced DNA damage response coupled with IFI16-driven ECM remodeling underlies dilated cardiomyopathy. (PubMed, Theranostics) - " W This study integrated bioinformatics analyses of human cardiac transcriptomic datasets with experimental validation in a doxorubicin-induced murine DCM model...Crucially, in vivo treatment with the DDR inhibitor NU7441 significantly attenuated IFI16 upregulation, ameliorated cardiac dysfunction, and decreased cardiac fibrosis markers...Pharmacological inhibition of the upstream DDR pathway effectively mitigates IFI16 induction, attenuates cardiac fibrosis, and improves cardiac function. This study identifies the DDR-IFI16-ECM remodeling axis as a crucial contributor to DCM pathogenesis and highlights its potential as a therapeutic target for mitigating adverse cardiac remodeling and dysfunction."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • IFI16 • TGFB1

CRISPR/Cas9 Ribonucleoprotein Delivery Enhanced by Lipo-Xenopeptide Carriers and Homology-Directed Repair Modulators: Insights from Reporter Cell Lines. (PubMed, Int J Mol Sci) - "The enhancement in genome editing by Nu7441 was widely applicable across several cell lines, several Cas9 RNP/ssDNA carriers (LAF-XPs), and also Cas9 mRNA/sgRNA/ssDNA polyplexes. These findings highlight a novel and counterintuitive role for Nu7441 as an enhancer of both HDR and total gene editing efficiency, presenting a promising strategy for Cas9 RNP-based gene therapy."

Journal • Preclinical • Gene Therapies

Enhancing radiation sensitivity in CHD5 dysregulated NSCLC by targeting NHEJ repair pathway (AACR 2025) - "Cell viability assays confirm that CHD5 depletion via siRNA in H460 NSCLC cells sensitizes them to ionizing radiation (IR) when combined with the DNA-PK inhibitor Nu7441, leading to increased cell death. In summary, CHD5 regulates NHEJ in NSCLC, and its depletion makes cancer cells more dependent on NHEJ for DNA repair. Targeting NHEJ in CHD5-deficient NSCLC cells offers a promising therapeutic strategy for enhancing the efficacy of radiation therapy in NSCLC."

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

Hyperglycemia-induced DNA damage response activates DNA-PK complex to promote endothelial ferroptosis in type 2 diabetic cardiomyopathy. (PubMed, Theranostics) - "Key DDR and ferroptosis markers were validated in cardiac microvascular endothelial cells (CMECs) isolated from mice with streptozotocin (STZ)/high-fat diet (HFD)-induced T2DM, with and without treatment with the DNA-PK inhibitors NU7441 or M9831. Our findings implicate the DNA-PK complex as a key regulator of hyperglycemia-induced endothelial ferroptosis in T2DM cardiomyopathy. Targeting DNA-PK complex may represent a novel therapeutic strategy for mitigating microvascular dysfunction and cardiac decline in T2DM."

Journal • Cardiomyopathy • Cardiovascular • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • ACSL4 • GPX4 • PACERR • PRKDC • PTGS2 • SLC7A11 • XRCC5 • XRCC6

An organotypic model for investigating drug-radiation responses in the lung. (PubMed, J Biol Methods) - "The slices were irradiated using 137Cs, either with or without a DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441)...In the organotypic model, radiation alone in DNA-PK-deficient SCID mice and radiation combined with DNA-PK inhibition in C57BL/6 mice led to increased residual γH2AX and 53BP1 staining. This study demonstrates that residual DNA damage levels following ionizing radiation in lung tissue are comparable between in vivo and ex vivo tissue slices, suggesting that PCLSs serve as a valuable organotypic model for investigating the effects of drug-radiation combinations."

Journal • Oncology • TP53BP1

DNA-PKcs Dysfunction Enhances the Antitumor Activity of Radioimmunotherapy by Activating the cGAS-STING Pathway in HNSCC. (PubMed, J Inflamm Res) - "The combination of a DNA-PK inhibitor (NU7441), radiation therapy, and a PD-1 checkpoint inhibitor showed improved antitumor effects and extended survival in mice...PRKDC alterations or DNA-PKcs dysfunction increased IR-induced DNA breaks, activating the cGAS-STING pathway and boosting the anti-tumor immune response. These findings suggest that targeting the DDR pathway may represent a promising therapeutic strategy and biomarker to improve the efficacy of radioimmunotherapy in HNSCC."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • PRKDC

p53-deficient cancer cells hyperactivate DNA double-strand break repair pathways to overcome chemotherapeutic damage and augment survival. (PubMed, Mol Biol Rep) - "Thus, our findings suggest that sustained DDR promotes chemoresistance and enhanced survival in p53-deficient cancer cells."

Journal • Oncology

Mitochondrial autophagy-related lncRNAs as prognostic biomarkers and therapeutic targets in gastric adenocarcinoma. (PubMed, Discov Oncol) - "Drug sensitivity analysis suggested that low-risk patients could benefit more from ICIs, Oxaliplatin, Irinotecan, Afatinib, and Dabrafenib, while high-risk patients showed higher sensitivity to IGF1R3801, JQI, WZ4003 and NU7441. The identified lncRNA-based risk model provides a reliable prognostic tool for GA patients and highlights distinct immune microenvironment profiles that may influence treatment responses. These findings contribute to developing personalized therapeutic strategies targeting lncRNAs and the TME in GA."

Biomarker • Journal • Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor

NU7441, a selective inhibitor of DNA-PKcs, alleviates intracerebral hemorrhage injury with suppression of ferroptosis in brain. (PubMed, PeerJ) - "Mechanistically, NU7441 attenuated neuronal apoptosis both in vivo and in vitro, alleviated oxidative stress by decreasing ROS levels, and suppressed ferroptosis by enhancing GPX4 activity. These results suggest that inhibition of DNA-PKcs is a promising therapeutic target for ICH."

Journal • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Vascular Neurology • GPX4

DNA-PK inhibition enhances neoantigen diversity and increases T cell responses to immunoresistant tumors. (PubMed, J Clin Invest) - "We identified DNA-PK inhibitor (DNA-PKi) NU7441 as a promising immunomodulator that reduced immunosuppressive proteins while increasing MHC-I expression in a panel of human melanoma cell lines...In patients, PRKDC levels inversely correlated with MHC I expression and CD8 TILs but positively correlated with increased neoantigen loads and improved responses to ICB. These studies suggest that inhibiting DNA-PK activity can restore tumor immunogenicity by increasing neoantigen expression and presentation and broadening the neoantigen-reactive T cell population."

IO biomarker • Journal • Tumor-specific neoantigens • Melanoma • Oncology • Solid Tumor • CD40 • CD8 • PRKDC • STING

Defining the role of Tip60 in the DNA damage response of glioma cell lines. (PubMed, Int J Radiat Biol) - "The interaction of Tip60 with ATM and DNA-PK was investigated using the specific inhibitors KU55933 and NU7441, respectively. Downregulation of Tip60 enhances the radiation sensitivity of both glioma cells and markedly elevates the radiation sensitivity when combined with DNA-PKi. Therefore, treatment with DNA-PK inhibitors represents a promising approach to augment the radiation sensitivity of glioma cell lines with deficient Tip60 activity in a synergistic manner."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • RAD51 • TP53BP1