KU-55933 / AstraZeneca - LARVOL DELTA

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

Targeting neurodevelopmental defects in Dravet syndrome mice rescues behaviour but not seizures and mortality. (AES 2024) - "Funding: - UCAJEDI (https://univ-cotedazur.fr/ucajedi-lidex-duniversite-cote-dazur, - ANR-15-IDEX-01, France), Laboratory of Excellence "Ion Channel Science and Therapeutics" - LabEx ICST (https://www.labex-icst.fr/en, ANR-11-LABX-0015-01, France) - EJPRD SCN1A-UP!...Furthermore, we assessed the importance of this developmental delay as pathological mechanism in Scn1a+/- mice rescuing GABA-switch by targeting either KCC2 or NKCC1 with the drugs KU55933 (KU) or bumetanide, respectively... We disclosed neurodevelopmental components in DS that selectively underlie some cognitive/behavioral defects, but not seizures, and we show that seizures and neuropsychiatric dysfunctions can be uncoupled and can have differential pathological mechanisms in DEEs. They could be treated separately with targeted pharmacological strategies."

Neurodevelopmental • Preclinical • CNS Disorders • Developmental Disorders • Epilepsy • Psychiatry • CDKN1A

Modulation of ATM enhances DNA repair in G2/M phase of cell cycle and averts senescence in Fuchs endothelial corneal dystrophy. (PubMed, Commun Biol) - "Remarkably, inhibiting ATM activation with KU-55933 restored DNA repair in G2/M phase and attenuated senescence in chronic cellular model of FECD lacking NQO1. This study provides insights into understanding the pivotal role of ATM in regulating cell-cycle, DNA repair, and senescence, in oxidative-stress disorders like FECD."

Journal • CNS Disorders • Mood Disorders • Ophthalmology • Transplantation • NQO1

Long noncoding RNA AK144717 exacerbates pathological cardiac hypertrophy through modulating the cellular distribution of HMGB1 and subsequent DNA damage response. (PubMed, Cell Mol Life Sci) - "Silencing AK144717 had a similar anti-hypertrophic effect to that of ATM inhibitor KU55933 and also suppressed the activated ATM-DDR signaling induced by hypertrophic stimuli...The binding of AK144717 to HMGB1 prevented the interaction between HMGB1 and SIRT1, contributing to the increased acetylation and then cytosolic translocation of HMGB1. Overall, our study highlights the role of AK144717 in the hypertrophic response by interacting with HMGB1 and regulating DDR, hinting that AK144717 is a promising therapeutic target for pathological cardiac growth."

Journal • Ataxia • Immunology • Movement Disorders • Primary Immunodeficiency • HMGB1 • SIRT1

HYPERAMMONEMIA INDUCES AN ATM-MEDIATED DNA DAMAGE RESPONSE IN CEREBELLAR AND HIPPOCAMPAL NEURONS (AASLD 2024) - "These results support that hyperammonemia can induce DSBs and ATM signaling in brain regions associated with HE and in HT22 cells. Therefore, strategies to mitigate the DDR, such as with KU55933, could be effective to alleviate ammonia-induced HE pathology."

Ataxia • CNS Disorders • Hepatic Encephalopathy • Hepatology • Immunology • Inflammation • Movement Disorders • Primary Immunodeficiency • CCL2

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

Persistent hypertension induces atrial remodeling and atrial fibrillation through DNA damage and ATM/CHK2/p53 signaling pathway. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "Additionally, inhibition of ATM with KU55933 (a specific ATM inhibitor) significantly reversed these effects. Collectively, these data demonstrate that DNA damage and the subsequently overactivated ATM/CHK2/p53 pathway play critical roles in hypertension-induced atrial remodeling and the susceptibility to AF. Targeting ATM/CHK2/p53 signaling may serve as a potential therapeutic strategy against AF."

Journal • Atrial Fibrillation • Cardiovascular • Fibrosis • Hypertension • Immunology • Inflammation • CHEK2

Sensitivity of Triple Negative Breast Cancer cells to ATM-dependent Ferroptosis Induced by Sodium Selenite. (PubMed, Exp Cell Res) - "Notably, Na2SeO3-induced ferroptosis was inhibited by ATM kinase inhibitor KU55933 or siATM, suggesting that Na2SeO3-induced ferroptosis was mediated by ATM protein in MDA-MB-231 cells. Our findings suggest a therapeutic strategy by ferroptosis against TNBC and deepened our understanding of ATM function."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • GPX4

ATM Activation is Key in Vasculogenic Mimicry Formation by Glioma Stem-like Cells. (PubMed, Biomed Environ Sci) - "For the examination of the function of pATM in VM formation by GSLCs, ATM knockdown by shRNAs and deactivated via ATM phosphorylation inhibitor KU55933 were studied...VM may predict a poor GBM prognosis and is associated with pATM expression. We propose that pATM promotes VM through extracellular matrix modulation and VE-Cadherin / pVEGFR-2 activation, thereby highlighting ATM activation as a potential target for enhancing anti-angiogenesis therapies for GBM."

Journal • Ataxia • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • CD31 • CDH5 • GFAP • PECAM1

Metformin combined with cisplatin reduces anticancer activity via ATM/CHK2-dependent upregulation of Rad51 pathway in ovarian cancer. (PubMed, Neoplasia) - "The standard first-line therapy for OC involves cytoreductive surgical debulking followed by chemotherapy based on platinum and paclitaxel. Using an ATM inhibitor, KU55933, effectively reversed the cisplatin resistance phenotype. In conclusion, our results suggest that met can antagonize the effects of cDDP in specific types of OC cells, leading to a reduction in the chemotherapeutic efficacy of cDDP."

Journal • Diabetes • Gynecologic Cancers • Metabolic Disorders • Oncology • Ovarian Cancer • Solid Tumor • CHEK2 • RAD51

Early inhibition of the ATM/p53 pathway reduces the susceptibility to atrial fibrillation and atrial remodeling following acute myocardial infarction. (PubMed, Cell Signal) - "The rat model of AMI was established by ligating left anterior descending coronary artery in the presence or absence of Ku55933 (an ATM kinase inhibitor, 5 mg/kg/d) treatment...Collectively, hyperactivation of ATM/p53 contributed to the pathogenesis of AF following AMI. Early intervention with ATM inhibitors substantially mitigated AF susceptibility and atrial electrical/structural remodeling, highlighting a novel therapeutic avenue against cardiac arrhythmia following AMI."

Journal • Ataxia • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure • Immunology • Inflammation • Movement Disorders • Myocardial Infarction • Primary Immunodeficiency • NLRP3

The DNA repair kinase ATM regulates CD13 expression and cell migration. (PubMed, Front Cell Dev Biol) - "Positive correlation was seen between ATM activity and CD13 protein expression using both "wildtype" (WT) and knockout (KO) ataxia telangiectasia (AT) cells through western blotting; with the same effect shown when treating neuroblastoma cancer cell line SH-SY5Y, as well as AT-WT cells, with ATM inhibitor (ATMi; KU55933)...This suggests an epistatic effect, and that both proteins may be acting in the same signaling pathway that influences cell migration. This work indicates a novel functional interaction between ATM and CD13, suggesting ATM may negatively regulate the degradation of CD13, and subsequently cell migration."

Journal • Ataxia • CNS Tumor • Immunology • Movement Disorders • Neuroblastoma • Oncology • Primary Immunodeficiency • Solid Tumor • Targeted Protein Degradation • ANPEP • MMP2 • MMP9

Kaempferol from Alpinia officinarum Hance induces G2/M cell cycle arrest in hepatocellular carcinoma cells by regulating the ATM/CHEK2/KNL1 pathway. (PubMed, J Ethnopharmacol) - "Collectively, our results revealed that kaempferol from A. officinarum inhibits the cell cycle by regulating the ATM/CHEK2/KNL1 pathway in HCC cells. In summary, our research presents an innovative supplementary strategy for HCC treatment."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Pain • Solid Tumor • BUB1 • CCNB1 • CDC25C • CDK1 • CHEK2 • GNRP • KNL1