NU7441 / AstraZeneca - LARVOL DELTA

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

Alternative Splicing and Non-Homologous End Joining Pathways Are Vulnerabilities Associated With Loss of The Tumor Suppressor TENT5C in Myeloma (IMW 2024) - "The AS inhibitors pladienolide B and isoginkgetin affected TENT5Cko cells at lower concentrations than TENT5Cwt cells (U266 TENT5Cko GI50=0.5 vs. TENT5Cwt GI50=1.4 nM, U266 TENT5Cko GI50=7.0 vs. TENT5Cwt GI50=13.7 µM, p< 0.001, respectively), as did NHEJ inhibitors STL127705 and NU7441 (U266 TENT5Cko GI50=22.5 vs. TENT5Cwt GI50=62.5 µM, U266 TENT5Cko GI50=9.5 vs. TENT5Cwt GI50=16.6 µM, p< 0.01)... Our results indicate a tumor suppressor role of TENT5C in MM, with antiproliferative properties and susceptibility to AS and NHEJ inhibitors."

Hematological Malignancies • Multiple Myeloma • Oncology • NT5C • SF3B1 • TENT5C

A manganese-doped layered double hydroxide loaded with lactate oxidase and DNA repair inhibitors for synergistically enhanced tumor immunotherapy. (PubMed, Acta Biomater) - "NU7441 prevents DNA damage repair, leading to an increased concentration of free DNA fragments, while Mn2+ ions activate the cGAS-STING pathway, enhancing the systemic anti-tumor immune response. The orchestrated immune-boosting nanoplatform effectively inhibits tumor growth and lung metastasis, presenting a promising strategy for cancer treatment."

Journal • Oncology • CGAS • STING

Discovery of the DNA-PKcs inhibitor DA-143 which exhibits enhanced solubility relative to NU7441. (PubMed, Sci Rep) - "Consistent with current inhibitors, inhibition of DNA-PKcs by DA-143 resulted in increased tumor cell sensitivity to DNA-damage from chemotherapy and inhibition of human T cell function. The improved solubility of DA-143 is critical for enhanced efficacy at reduced doses and facilitates more effective evaluation of DNA-PKcs inhibition in both preclinical and clinical development."

Journal • Immunology • Oncology

Comprehensive bioinformatics analysis and cell line experiments revealed the important role of CDCA3 in sarcoma. (PubMed, Heliyon) - "Finally, patients with high CDCA3 expression in sarcoma were analyzed for resistance to NU7441 and others, while sensitive to Fulvestrant and Dihydrorotenone. These results suggest for the first time that knockdown of CDCA3 may inhibit sarcoma progression. CDCA3 may be an effective target for the treatment of sarcoma."

Journal • Preclinical • Inflammatory Arthritis • Oncology • Sarcoma • Solid Tumor • CD8 • CDCA3 • CDCA8

Chloroquine-induced DNA damage synergizes with DNA repair inhibitors causing cancer cell death. (PubMed, Front Oncol) - "Cell death caused by chloroquine/Panobinostat combination were significantly reduced by N-Acetylcysteine, a reactive oxygen species scavenger, underscoring the pivotal role of DSB generation in CQ/LBH-induced lethality. Based on these data, we also explored the combination of CQ with KU-57788 and NU-7026, two inhibitors of the other main DSB repair pathway, nonhomologous end joining (NHEJ), and again synergistic effects on apoptosis induction were observed. Our data provide a rationale for the clinical investigation of CQ in combination with DSB inhibitors for the treatment of different solid tumors."

Journal • Brain Cancer • Breast Cancer • CNS Tumor • Colorectal Cancer • Gastrointestinal Cancer • Glioblastoma • Head and Neck Cancer • Oncology • Solid Tumor

TRIM24 Cooperates with Ras Mutation to Drive Glioma Progression through snoRNA Recruitment of PHAX and DNA-PKcs. (PubMed, Adv Sci (Weinh)) - "Targeting DNA-PKcs with the small molecule inhibitor NU7441 synergizes with temozolomide to reduce Ep-GBM tumorigenicity and prolong animal survival. These findings provide new insights into the epigenetic regulation of Ep-GBM-like transformation and suggest a potential therapeutic strategy for patients with Ep-GBM."

Journal • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • RAS • TP53 • TRIM24

DNA-PKcs/AKT1 inhibits epithelial-mesenchymal transition during radiation-induced pulmonary fibrosis by inducing ubiquitination and degradation of Twist1. (PubMed, Clin Transl Med) - "Our study clarified the critical role and mechanism of DNA-PKcs in RIPF and showed that it could be a potential target for preventing RIPF."

Journal • Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • AKT1 • IGF1 • TWIST1

ARF4-mediated retrograde trafficking as a driver of chemoresistance in GBM. (PubMed, Neuro Oncol) - "Our findings demonstrate that ARF4-mediated retrograde trafficking contributes to the development of TMZ resistance, cementing this pathway as a viable strategy to overcome chemoresistance in GBM."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • STAT1

Improving the Efficiency of CRISPR Ribonucleoprotein-Mediated Precise Gene Editing by Small Molecules in Porcine Fibroblasts. (PubMed, Animals (Basel)) - "The results showed that the optimal concentrations of the small molecules, including L-189, NU7441, SCR7, L755507, RS-1, and Brefeldin A, for in vitro-cultured PFFs' viability were determined...There are no benefits in using the combination of two small molecules, since none of the combinations improved the precise gene editing efficiency compared to single small molecules. In conclusion, these results suggested that a single small molecule can increase the efficiency of CRISPR RNP-mediated precise gene editing in porcine cells."

Journal • Preclinical