KU-55933 / AstraZeneca - LARVOL DELTA

Non-canonical ATR signaling mediates direct and bystander cold atmospheric plasma-induced stress responses in A549 lung adenocarcinoma cells. (PubMed, Sci Rep) - "Mechanistically, pharmacological inhibition of ATR (with NU6027), but not ATM (with KU-55933) significantly attenuated bystander response. This indicates a non-canonical ATR mediated model of bystander CAP signaling, possibly through release of soluble factors to neighbouring cells. Collectively, the findings challenge the classical 'direct-action' paradigm by demonstrating ionizing radiation-like bystander effects for non-ionizing CAP and highlights ATR as a potential therapeutic target to improve the efficacy of CAP-based cancer treatment."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Hepatitis B virus X protein induces E6-associated protein-mediated proteasomal degradation of p53 phosphorylated at Ser-15. (PubMed, J Gen Virol) - "E6AP-mediated p53 degradation was severely impaired in the presence of the ATM inhibitor KU-55933, indicating that HBx-induced p53 phosphorylation plays a critical role in this process. Additionally, E6AP could target p53 phosphorylated by DNA-damaging agents like etoposide in the absence of HBx...Ser-15 phosphorylation was pivotal, as E6AP could degrade p53 S15D (phosphomimetic mutant) but failed to act on p53 S15A (a non-phosphorylatable mutant). These findings suggest that HBx-induced p53 phosphorylation enhances E6AP-mediated degradation while concurrently inhibiting MDM2-mediated pathways, thereby fine-tuning p53 levels to support cell survival, viral replication and potentially carcinogenesis during HBV infection in human hepatocytes."

Journal • Ataxia • Hepatitis B • Immunology • Infectious Disease • Inflammation • Movement Disorders • Oncology • Primary Immunodeficiency • Targeted Protein Degradation • CHEK2

TARGETING THE DNA DAMAGE RESPONSE IN DORMANT MYELOMA CELLS (EHA 2026) - "When tumour burden was high mice were treated with chemotherapy 50mg/kg lenalidomide and 0.75mg/kg bortezomib...Activity of DNA damage response inhibitor drugs (olaparib, abemaciclib, berzosertib and Ku55933) on dormant and proliferating myeloma cells was assessed using resazurin viability assay after 1 week of treatment...Summary/Conclusion Dormant myeloma cells exhibit higher levels of DNA damage across modelling approaches. Thus, targeting the DNA damage response is a promising approach to target chemo-resistant dormant myeloma cells."

Hematological Malignancies • Multiple Myeloma • AXL • BRCA • CDKN1A

Dormant myeloma cells exhibit higher DNA damage levels – a new vulnerability in cancer cell dormancy? (EACR 2026) - "Study 1 did not incur any treatment and study 2 used standard of care (SOC) chemotherapy 50mg/kg lenalidomide and 0.75mg/kg bortezomib...Activity of DNA damage response inhibitor drugs (olaparib, abemaciclib, berzosertib and Ku55933) on proliferating myeloma cells was investigated using resazurin viability assay 1 week after dosing... Dormant myeloma cells exhibit higher levels of DNA damage across in vitro and in vivo modelling approaches. Thus, targeting the DNA damage response could be a promising new approach to target chemo-resistant dormant myeloma cells."

Hematological Malignancies • Multiple Myeloma • Oncology • ANXA5 • AXL • BRCA • CDKN1A

RNA Helicase DDX21 Controls CD4+ T Cell Proliferation and Promotes Inflammatory Bowel Disease via Translational Control. (PubMed, Adv Sci (Weinh)) - "Given this dependence on ribosome biogenesis, pharmacological targeting of this pathway via KU55933-an inhibitor of ribosome synthesis-related signaling-recapitulated the protective effects of DDX21 loss: KU55933 alleviated dextran sulfate sodium (DSS)-induced colitis in mice and attenuated pathogenic CD4+ T cell expansion. Our findings establish DDX21 as a key regulator of T cell proliferation and highlight its potential as a therapeutic target for IBD and other autoimmune disorders."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • CD4 • DDX21

ATM inhibition restores IFN-γ sensitivity and induces ferroptosis in NSCLC via DNA damage response. (PubMed, Biochem Biophys Rep) - "Given the critical role of the serine/threonine kinase ataxia telangiectasia mutated (ATM) in detecting DNA double-strand breaks and coordinating HR repair, we investigated whether ATM contributes to IFN-γ resistance by using the ATM inhibitor KU-55933...Mechanistically, the combination of IFN-γ treatment and ATM inhibition elicited a robust DNA damage response and disrupted glutathione metabolism, reducing the GSH/GSSG ratio and thereby promoting ferroptosis through increased susceptibility to oxidative stress. These findings highlight the pivotal role of DNA damage response pathways in mediating the anti-tumor effects of IFN-γ."

IO biomarker • Journal • Ataxia • Immunology • Lung Cancer • Movement Disorders • Non Small Cell Lung Cancer • Oncology • Primary Immunodeficiency • Solid Tumor • IFNG

Hepatitis C Virus Core Induces p53 Ser-15 Phosphorylation to Facilitate E6-Associated Protein-Mediated Proteasomal Degradation of p53. (PubMed, Cells) - "Proteasomal inhibition with MG132 confirmed that HCV Core and E6AP act together to regulate p53 levels via the proteasome. Importantly, HCV Core-induced p53 phosphorylation was essential for E6AP-mediated degradation, as shown by the impairment of degradation in the presence of the ATM inhibitor KU-55933. E6AP also targeted p53 phosphorylated at Ser-15 by etoposide, as well as phosphomimetic mutants such as p53 S15D, but not non-phosphorylatable mutants such as p53 S15A. These findings suggest that HCV Core-induced p53 phosphorylation enhances E6AP-mediated degradation while preventing MDM2 from targeting p53, thereby maintaining p53 levels that support cell survival, viral replication, and potentially oncogenesis in human hepatocytes."

Journal • Hepatitis C • Infectious Disease • Inflammation • Oncology • Targeted Protein Degradation • CHEK2

Homologous Recombination and Alternative End-Joining Repair Pathways are Important Determinants of Radiosensitivity to Proton Radiotherapy. (PubMed, Int J Radiat Oncol Biol Phys) - "The observed genotype-specific or drug-induced increase in radiosensitivity towards proton beam radiotherapy highlights the promise of genetic profiling of DSB repair defects for biology-driven patient stratification and the use of PARP-inhibitors in guiding personalized proton radiotherapy strategies."

Journal • Oncology • ANXA5 • BRCA2

Increased sensitivity of etoposide-treated breast cancer cells with an ATM inhibitor. (PubMed, PLoS One) - "The FDA approval of Olaparib, a specific PARP inhibitor for BRCA-mutated breast cancer patients, has motivated researchers to explore other synthetic lethal interactions that could increase DNA damage accumulation, leading to cancer cell death. We found that targeting ETO-treated breast cancer cells with an ATM kinase inhibitor, KU-55933 (KU) induced higher chromosomal damage/aberrations, as evaluated by the cytokinesis-block micronucleus assay. The ATM kinase inhibitor also significantly reduced the viability of ETO-treated breast cancer cells."

Journal • Breast Cancer • Oncology • Solid Tumor • BRCA • HRD

ATM promotes bone metastatic propensity of breast cancer by inducing osteoclastogenesis via the NFκB-CCL2 pathway. (PubMed, Acta Pharmacol Sin) - "In vivo experiments confirmed that ATM knockout (ATM KO) or treatment with small-molecule ATM inhibitor KU55933 markedly inhibited osteoclastogenesis of SK-BR-3 cells and the progression of breast cancer bone metastasis. Our results underscore the pivotal role of ATM in regulating NFκB-CCL2 expression and promoting the progression of breast cancer bone metastasis."

Journal • Ataxia • Breast Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • CCL2

Ataxia-telangiectasia mutated activation mediates transforming growth factor beta signaling in acetaminophen-induced liver injury in mice. (PubMed, Physiol Rep) - "Pretreatment with an ATM inhibitor, KU55933, attenuated APAP-induced hepatocyte damage and resulted in attenuated mothers against decapentaplegic homolog 2/3 (SMAD2/3) signaling with no changes in activated TGFβ1 levels, suggesting that ATM activation modulates TGFβ1 signaling via post-translational mechanisms. APAP was found to promote transforming growth factor beta receptor 2 (TGFβRII) stabilization through activation of phosphorylated casitas B-lineage lymphoma (p-c-cbl) and subsequent neddylation of TGFβRII, which was attenuated by inhibitors of ATM signaling or neddylation machinery. In conclusion, APAP-induced hepatic DNA damage activates an ATM-mediated response that enhances TGFβ1 signaling through stabilization of TGFβRII, and inhibition of ATM consequently reduces APAP-induced hepatic injury."

Journal • Preclinical • Ataxia • Hematological Malignancies • Hepatology • Immunology • Liver Failure • Lymphoma • Movement Disorders • Oncology • Primary Immunodeficiency • CHEK2 • SMAD4 • TGFBR2

Comprehensive multi-omics data to construct hepatocellular carcinoma pathway subtypes and classification model. (PubMed, Comput Biol Chem) - "Moreover, our analysis identified six subtype-specific drugs, such as KU_55933 and Cyclophosphamide, that were more sensitive to PS1. In conclusion, this study successfully constructed and evaluated a pathway-based molecular subtype and classification model for HCC, thoroughly investigated the biological and multi-omics differences between subtypes. Additionally, the identification of three telomere-associated biomarkers offers guidance and a theoretical basis for personalized treatment and clinical use of drugs for HCC patients."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • POLD1 • TERF1

Diversity of oxidative stress and senescence phenotypes induced by chemotherapeutic agents in HUVECs. (PubMed, Sci Rep) - "HUVECs were treated with DNA crosslinkers (doxorubicin, mitomycin C), topoisomerase inhibitors (etoposide, camptothecin), and methotrexate (MTX)...ROS scavenger Mito-Q and ATM inhibitor KU55933 were co-administered to evaluate their modulatory effects...Chemotherapeutic agents triggered endothelial senescence via DNA damage and ROS accumulation, with heterogeneity in potency and mechanisms. ROS scavengers may mitigate methotrexate-associated vascular toxicity, and targeting ROS could enhance chemotherapy safety by preserving endothelial function."

Journal • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • TP53BP1

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

Identification of biomarkers associated with mitophagy in bladder cancer. (PubMed, Sci Rep) - "A total of 135 drugs differed in sensitivity between HRG and LRG, including KU.55933...Expression analysis showed that CTSK was significantly downregulated in the BLCA group, while MTERF3, SRC, and CSNK2B were significantly upregulated. In conclusion, CTSK, MTERF3, SRC, and CSNK2B laid the foundation for targeted therapy in the treatment of BLCA."

Biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CTSK • MIR149 • TP53

ATM inhibitors in cancer radiotherapy: Mechanisms, clinical development, and future directions. (PubMed, Eur J Med Chem) - "Inhibitors such as KU-55933, KU-60019, and AZD1390 have shown the potential to sensitize cancer cells to radiotherapy by impairing DNA repair, thereby enhancing treatment efficacy...Currently, none have gained approval from the FDA or EMA, but six candidates, AZD1390, AZD0156, ZN-B-2262, SYH2051, WSD0628 and M3541 are in clinical trials, often as adjuncts to radiotherapy or in combination with PARP inhibitors. Their safety and effectiveness, however, are still under investigation. This review synthesizes ATM's dual roles and the therapeutic promise of targeting ATM in cancer radiotherapy."

Journal • Review • Ataxia • Brain Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • CDKN1A • CHEK1 • CHEK2

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

Investigation of key ferroptosis-associated genes and potential therapeutic drugs for asthma based on machine learning and regression models. (PubMed, Sci Rep) - "Additionally, KU-55933 was identified as a potential small-molecule inhibitor of AGPS, with stable binding confirmed through computational simulations. These findings emphasize the role of ferroptosis-related genes in asthma and propose promising therapeutic candidates, providing novel insights into its diagnosis and treatment."

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

DNA damage response of U2OS cells to low doses of gamma radiation delivered at very low dose rate. (PubMed, DNA Repair (Amst)) - "Gene expression was modulated by AD. In conclusion, AD differentially modulated the response of cells when given alone and after the CD, in absence and presence of KU-55933."

Journal • TP53BP1

Disruption of ATR Signaling by Epstein-Barr Virus Latent Membrane Protein 1 Sensitizes Nasopharyngeal Carcinoma Cells to Cisplatin. (PubMed, J Med Virol) - "Inhibition of ATR (VE821 or AZD6738), but not ATM (KU55933 or AZD0156), phenocopied the G1 arrest and hypersensitivity. Publicly available RNA-sequencing data from microdissected NPC tumors showed that LMP1 expression in the primary tumors was the lowest in cisplatin-treated patients that experienced recurrence. These findings could have clinical significance in stratifying NPC patients such that tumors with limited or variable LMP1 expression might benefit from ATR inhibitor therapy."

Journal • Epstein-Barr Virus Infections • Immunology • Infectious Disease • Nasopharyngeal Carcinoma • Oncology • Solid Tumor

Acetyl alkannin, a Shikonin monomer, inhibits the ATM/DDR pathway by targeting ATM and sensitizes cisplatin in solid tumors. (PubMed, Chem Biol Interact) - "In vitro assays showed that DDP activated ATM to initiate the downstream DDR, thereby promoting chemoresistance; inhibition of ATM using KU-55933 or siRNA enhanced the anticancer effect of DDP. In vivo xenograft experiments confirmed the superior tumor growth inhibition of the combination treatment. These findings establish ATM-mediated DDR activation as a central mechanism of DDP resistance and identify acetyl alkannin as a candidate sensitizer for platinum-based chemotherapy."

Journal • Liver Cancer • Lung Cancer • Oncology • Solid Tumor • RAD51

Combining photodynamic therapy and ATM inhibition using modified bovine serum albumin: A co-delivery nano platform for eliciting pyroptosis and apoptosis to fuel TNBC therapy. (PubMed, Int J Biol Macromol) - "Herein, an "all-in-one" tumor-therapeutic nanomedicine named HA@IR780@KU55933@BSA (HIKB) which integrated photosensitizer IR780 with ATM kinase inhibitor KU55933 was designed to facilitate drug delivery and target specific pathways involved in tumor PDT treatment resistance...In vivo evaluations in the TNBC orthotopic xenograft mouse model demonstrated that the designed HIKB NPs could accumulate in tumor tissues and exert synergistic therapeutic effects. Altogether, this study described a self-assembling strategy for constructing an all-in-one nanomedicine that effectively integrates multiple therapeutic modalities to provide a comprehensive and systemic approach to tumor suppression."

Journal • Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Triple Negative Breast Cancer • CASP3 • GSDME

Integrative analysis of cuproptosis-related lncRNAs for prognostic risk assessment and tumor immune microenvironment evaluation in laryngeal squamous cell carcinoma. (PubMed, Int J Biol Macromol) - "GIHCG's competing endogenous RNAs (ceRNA) and co-expression networks (CEN) were established, revealing sensitivity to drugs like BMS-509744, YM155, and KU-55933...Moreover, METTL16-mediated m6A methylation regulates GIHCG expression. In conclusion, this study successfully established a prognostic model comprising nine cuproptosis-related lncRNAs, accurately predicting LSCC prognosis, and highlighted the crucial role of GIHCG as a novel nucleic acid biomarker in regulating LSCC progression."

Journal • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • METTL16 • SNHG12

Neurodevelopmental defects in Dravet syndrome Scn1a+/- mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality. (PubMed, Neurobiol Dis) - "Using a multi-scale approach, here we show that targeting GABA-switch with the drugs KU55933 (KU) or bumetanide (which upregulate KCC2 or inhibits NKCC1 chloride transporters, respectively) rescues social interaction deficits and reduces hyperactivity observed in P21 Scn1a+/- DS mouse model. Our work provides further evidence that seizures and neuropsychiatric dysfunctions in DEEs can be uncoupled and can have differential pathological mechanisms. They could be treated separately with targeted pharmacological strategies."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Epilepsy • Genetic Disorders • Psychiatry • CDKN1A • NAV1

Hepatitis B virus hijacks MRE11-RAD50-NBS1 complex to form its minichromosome. (PubMed, PLoS Pathog) - "Interestingly, Mirin, a MRN complex inhibitor which can inhibit the exonuclease activity of MRE11 and MRN-dependent activation of ATM, but not ATM kinase inhibitor KU55933, could decrease cccDNA level...In summary, we identified host factors, specifically the MRN complex, regulating cccDNA formation during HBV infection. These findings provide insights into how HBV hijacks host enzymes to establish chronic infection and reveal new therapeutic opportunities."

Journal • Fibrosis • Hepatitis B • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cancer • Liver Cirrhosis • Oncology • Solid Tumor • RAD50