NU7441 / AstraZeneca - LARVOL DELTA

Pan-cancer multi-omics machine learning defines a lactylation-associated immune-excluded tumor state with proteomic and experimental corroboration. (PubMed, Comput Biol Chem) - "Lactylation-program-associated transcriptional patterns delineate a recurrent immune-excluded pan-cancer tumor state associated with adverse prognosis, reduced predicted immunotherapy responsiveness, exploratory single-cancer protein-level support, and testable DNA damage response-targeting hypotheses. LacCoEx-Atlas and LARItools provide open resources for lactylation-program-associated tumor-state stratification and future translational research."

IO biomarker • Journal • Bladder Cancer • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • CD8 • HDAC4 • KDM6B • NSD3

L3MBTL4 methylation is a sensitive marker of DNA-PK inhibitor in pancreatic cancer. (PubMed, Explor Target Antitumor Ther) - "Loss of L3MBTL4 increased the sensitivity of PDAC cells to NU7441 both in vitro and in vivo. L3MBTL4 is a new component of NHEJ signaling and epigenetic silencing of L3MBTL4 sensitizes PDAC cells to DNA-PK inhibitors, providing a potential new therapeutic strategy."

Journal • Brain Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Molecular subtyping and therapeutic drug prediction in esophageal squamous cell carcinoma based on manganese-metabolism-related genes. (PubMed, Arab J Gastroenterol) - "MMRG-based subtyping and the reliable prognostic risk score model provide novel insights for predicting prognosis and developing personalized therapy in ESCC."

IO biomarker • Journal • Esophageal Squamous Cell Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • PD-1 • SLC40A1 • TIGIT

A Tale of Two Cell Lines: Characterization of Differential Efficacy of Small Molecule Drugs Cediranib and NU-7441 on Primary Versus Metastatic Colorectal Cancer. (PubMed, Pharmacol Res Perspect) - "An SW620 line grown in non-attachment plates and then reattached (SW620F) exhibited high DNA-PKcs activation and drug sensitivity. Correlation between drug response and gene expression crucial to cell growth and successful metastasis may reveal new biomarkers to target potential treatments."

Journal • Preclinical • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor • PROM1 • TGM2

Identification of a novel ion channel-related gene signature to predict prognosis and immune response of gastric cancer. (PubMed, Transl Cancer Res) - "Evaluations of immune infiltration patterns and drug susceptibility in cohorts stratified by high versus low ICRGRS revealed that elevated ICRGRS instances featured an immunosuppressive tumor microenvironment and displayed superior gains from ZM447439, RO-3306, NU7441, BMS-754807, and JQ1. On the other hand, low-ICRGRS cases showed increased efficacy toward immunotherapies and conventional GC agents like Oxaliplatin and 5-fluorouracil...CNGB3 knockdown significantly suppressed the malignant phenotype of GC cells. Our findings furnish innovative viewpoints on outcome forecasting and therapeutic targets of GC through the lens of ion channels."

Gene Signature • IO biomarker • Journal • Gastric Cancer • Oncology • Solid Tumor

Oncolytic HSV Synergizes with DNA-PKcs Inhibition to Abrogate Stemness and DNA Repair in Glioblastoma (ASGCT 2026) - "DNA-PKcs pharmacological inhibitors included NU7441, AZD7648, VX-984, and predominantly M3814 (Peposertib), a selective, brain-penetrant inhibitor currently in clinical trial...GSCs transduced with doxycycline-inducible DNA-PKcs shRNA were used to validate selectivity...Integrating DDR inhibition with oHSV therapy simultaneously attacked stemness and DNA repair, two critical survival pathways, offering a novel synthetic lethal-like approach. These results warrant further clinical investigation of oHSV and DNA-PKcs inhibitors in GBM and potentially other solid tumors."

Brain Cancer • Glioblastoma • Herpes Simplex • Infectious Disease • Solid Tumor • MYC • SOX2

A computational framework identifies a matrisome-related gene signature for bladder cancer prognosis and prioritizes candidate compounds. (PubMed, Comput Biol Chem) - "This study highlights the prognostic relevance of MRGs in BLCA. The nine-gene signature may serve as a useful framework for risk stratification in BLCA, while the identified risk genes and candidate compounds provide a basis for further biological and experimental investigation rather than direct therapeutic inference."

Gene Signature • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CD3D • CLDN5 • RBP7 • SERPINE2 • TSPAN8

Direct coupling and protective activation of DRP1 by the DNA-PKcs inhibitor KU-57788 synergizes with ferroptosis in anaplastic thyroid cancer cells. (PubMed, Cell Death Dis) - "Collectively, our findings highlight the therapeutic potential of KU-57788 in ATC while revealing an intrinsic resistance mechanism mediated by DRP1 activation and the potential involvement of the NRF2/SLC7A11/GSH axis. More importantly, we provide strong evidence that combining KU-57788 with ferroptosis inducers significantly enhances its anticancer efficacy, offering a promising therapeutic strategy for ATC."

Journal • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • SLC7A11

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

Epigenetic silencing L3MBTL4 sensitizes esophageal cancer to DNA-PKcs inhibitor. (PubMed, Cancer Biol Ther) - "Epigenetic silencing of L3MBTL4 sensitized ESCC cells to NU7441, a DNA-PKcs inhibitor, both in vitro and in vivo. L3MBTL4 is a potential tumor suppressor and methylation of L3MBTL4 is a sensitive marker of DNA-PKcs inhibitors."

Journal • Brain Cancer • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Infectious Disease • Oncology • Solid Tumor • Squamous Cell Carcinoma

Construction and evaluation of a bladder cancer prognosis model based on super-enhancer-associated genes. (PubMed, Discov Oncol) - "Three genes (MXRA7, PLEKHG4B and ATP2B4) were identified to construct a SERG-related model in BLCA, which provides a basis for understanding BLCA pathogenesis and new insights into BLCA treatment."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CD4 • CD8 • KRAS • MXRA7

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