AZD0156 / AstraZeneca - LARVOL DELTA

ATM and p53 in aging and cancer: a double-edged sword in genomic integrity. (PubMed, Biogerontology) - "Chemical small molecule p53 activators (PRIMA-1, Nutlin-3) and ATM inhibitors (AZD0156, M4076) sensitize cancer to DNA damaging therapy in cells and nude mice without p53. In this review, we consolidate state-of-the-art findings on ATM and p53 coordination in the processes involved in DNA repair, apoptosis, and senescence to show how ATM and p53 dual involvement in tumor suppression and cancer progression is occurring. It also focuses on therapeutic approaches targeting these pathways to benefit from senescence and intimidating cancer treatment outcomes."

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

The ATM Kinase Inhibitor AZD0156 is a Potent Inhibitor of Plasmodium Phosphatidylinositol 4-Kinase (PI4Kβ) and is an Attractive Candidate for Medicinal Chemistry Optimisation Ag…. (PubMed, Angew Chem Int Ed Engl) - "Importantly, a cleaner biochemical profile was measured against human kinases (MAP4K4, MINK1) implicated in embryofoetal developmental toxicity associated with the PfPI4Kβ inhibitor MMV390048. This improved kinase selectivity profile and structural differentiation from other PI4Kβ inhibitors, together with its multistage antiplasmodial activity and favourable pharmacokinetic properties, makes AZD0156 an attractive candidate for target-based drug repositioning against malaria via a medicinal chemistry optimisation approach."

Journal • Ataxia • Immunology • Infectious Disease • Malaria • Movement Disorders • Oncology • Primary Immunodeficiency

Patient-Derived Organoids of anal cancer as a translational tumor model (ESTRO 2025) - "Further investigations revealed an enhanced response to irradiation with a combined treatment of AZD0156, afatinib, and alpelisib, particularly in PMU 616 and 363. To the best of our knowledge, we demonstrated for the first time the successful establishment and cultivation of patient-derived anal carcinoma organoids. This offers a new possibility in radiobiological research in this rare tumor entity and forms the basis for further translational studies."

Preclinical • Anal Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • CDKN1B • PDGFRB • PIK3CA

HUWE1-mediated ubiquitination and degradation of oxidative damage repair gene ATM maintains mitochondrial quality control system in lens epithelial cells. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "In a SD rat lens model ex vitro, the ATM inhibitor AZD0156 exacerbated lens opacity, whereas the mitochondrial fission inhibitor Mdivi-1 restored lens transparency. These results suggest that modulating key molecules involved in oxidative damage repair and mitochondrial fission pathways could enhance mitochondrial quality control, paving the way for the development of targeted molecular therapies for the prevention and treatment of ARCC."

Journal • Cataract • Metabolic Disorders • Ophthalmology • Targeted Protein Degradation • ATM • HUWE1

Cyclin D1 Overexpression in Mantle Cell Lymphoma Causes Cellular Dependence on Microhomology-Mediated End-Joining (ASH 2024) - "As expected, genetic deletion or pharmacological inhibition (ART558 and novobiocin) of POLQ in MCL cells led to increased RS and increased unrepaired DNA damage during mitosis, ultimately leading to chromosomal instability, mitotic catastrophe, and apoptosis...When POLQ was inhibited, a significant antitumor effect was evident in MCL cells, including ibrutinib-resistant MCL, both in vitro and in vivo, and this effect was enhanced by ATM deficiency. Further, simultaneous inhibition of both ATM (AZD0156) and POLQ was synthetic lethal in MCL cell lines and primary tumor cells from patients with MCL...Within MCL, POLQ is crucial in mitigating the adversities of CCND1-driven RS. Our data suggest that targeting the MMEJ pathway via POLQ inhibition, particularly in the presence of CCND1 overexpression and ATM deficiency, emerges as a promising therapeutic approach in oncoprotein-driven hematologic malignancies such as MCL."

Hematological Disorders • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ATM • CCND1 • HRD • POLQ

PPM1G Inhibits Epithelial-Mesenchymal Transition in Cholangiocarcinoma by Catalyzing TET1 Dephosphorylation for Destabilization to Impair Its Targeted Demethylation of the CLDN3 Promoter. (PubMed, Adv Sci (Weinh)) - "Two phosphatase inhibitors, staurosporine and AZD0156, inhibit epithelial-to-mesenchymal transition (EMT) in cholangiocarcinoma cells by suppressing TET1 expression. In conclusion, it is also demonstrated that PPM1G can be employed as a therapeutic target to impede the progression of CCA by catalyzing the dephosphorylation of TET1, which diminishes the capacity of TET1 to target the CLDN3 promoter to activate transcription and inhibit EMT in CCA."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • CLDN3 • PPM1G • TET1

Inhibition of ATM or ATR in combination with hypo-fractionated radiotherapy leads to a different immunophenotype on transcript and protein level in HNSCC. (PubMed, Front Oncol) - "The toxic and immunogenic effects of the smKI AZD0156 (ATMi) and VE-822 (ATRi) in combination with a hypo-fractionated scheme of 2x5Gy RT on HPV-negative (HSC4, Cal-33) and HPV-positive (UM-SCC-47, UD-SCC-2) HNSCC cell lines were analyzed as follows: cell death (necrosis, apoptosis; detected by AnxV/PI), expression of immunostimulatory (ICOS-L, OX40-L, TNFSFR9, CD70) and immunosuppressive (PD-L1, PD-L2, HVEM) checkpoint marker using flow cytometry; the release of cytokines using multiplex ELISA and the gene expression of Cal-33 on mRNA level 48 h post-RT. This includes pro-inflammatory signaling induced by RT + ATRi but also anti-inflammatory signals. These findings were confirmed by RNAseq analysis, which further highlighted the immune-suppressive nature of RT + ATMi."

Combination therapy • IO biomarker • Journal • Head and Neck Cancer • Immunology • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD70 • CXCL8 • EDIL3 • ICOS • IL6 • PD-L1 • PD-L2

Inhibition of ATM or ATR in combination with hypo-fractionated radiotherapy leads to a different immunophenotype on transcript and protein level in HNSCC (Front Oncol) - "The toxic and immunogenic effects of the smKI AZD0156 (ATMi) and VE-822 (ATRi) in combination with a hypo-fractionated scheme of 2x5Gy RT on HPV-negative (HSC4, Cal-33) and HPV-positive (UM-SCC-47, UD-SCC-2) HNSCC cell lines were analyzed....The immune phenotype of cancer cells, not dying from combination therapy itself, is altered predominantly by RT+ATRi in an immune-stimulatory manner by the up-regulation of ICOS-L. However, the analysis of secreted cytokines after treatment of HNSCC cell lines revealed an ambivalent influence of both inhibitors, as we observed the intensified secretion of IL-6 and IL-8 after RT+ATRi."

Preclinical • Squamous Cell Carcinoma of Head and Neck

Inhibition of aberrantly overexpressed Polo-like kinase 4 is a potential effective treatment for DNA damage repair-deficient uterine leiomyosarcoma. (PubMed, Clin Cancer Res) - "Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacological inhibition of ATM enhanced the efficacy of PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy."

Journal • Ataxia • Immunology • Leiomyosarcoma • Movement Disorders • Oncology • Primary Immunodeficiency • Sarcoma • Solid Tumor • Uterine Corpus Leiomyosarcoma • BRCA2 • PLK4

Epigenetic silencing schlafen-11 sensitizes esophageal cancer to ATM inhibitor. (PubMed, World J Gastrointest Oncol) - "SLFN11 is frequently methylated in human ESCC. Methylation of SLFN11 is sensitive marker of ATM inhibitor in ESCC."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Cancer • Oncology • Squamous Cell Carcinoma • SLFN11

A multifaceted study of X-Ray radiation therapy across diverse mouse tumor models (AACR 2024) - "The results show that X-ray radiation has anti-tumor effects across diverse models, with combination drug treatment with both Gemcitabine and AZD0156 showing enhanced therapeutic effects. Furthermore, pRAD50 showed decreasing trend in the single dose PD study in HCC1975-luc intracranial model. We conclude that our platform provides robust methods for evaluating the therapeutic effects of X-Ray radiation, offering invaluable insights for the creation of new cancer therapies."

Preclinical • Gastrointestinal Cancer • Liver Cancer • Oncology • Solid Tumor

Computational Analysis of Non-synonymous SNPs in ATM Kinase: Structural Insights, Functional Implications, and Inhibitor Discovery. (PubMed, Mol Biotechnol) - "Molecular docking and dynamic simulation analyses highlight strong binding affinities of quercetin for Y2080D and AZD0156 for C2770G, suggesting potential therapeutic options...The study underscores the significance of Y2080D and C2770G mutations, offering valuable insights for future precision medicine targeting-specific ATM. Despite informative computational analyses, a significant research gap exists, necessitating essential in vitro and in vivo studies to validate the predicted effects of ATM mutations on protein structure and function."

Journal • Ataxia • Hematological Malignancies • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Squamous Cell Carcinoma • ATM

Investigation of Radiation Sensitization in Patient-Derived Head and Neck Squamous Cell Carcinoma Organoids (DKK 2024) - "A radiosensitizing effect can be confirmed after treatment with AZD0156, Afatinib or Alpelisib in three organoid lines using this assay so far. Establishment of HNSCC organoids was successful using our workflow. These 3D models can be used to screen for potential radiosensitizers. For validation, we established an organoid formation assay to determine the clonogenic survival as an important endpoint in radiobiology."

Clinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PIK3CA • TP53

Multimodal treatment of HNSCC with RT and ATR inhibitor VE-822 alters the tumor cell phenotype (ETHNC 2024) - "Cells were treated with either 1 µM AZD0156 (ATM inhibitor) or 0.1 µM VE822 (ATR inhibitor) alone or in combination with RT (2x5Gy). Both inhibitors induce significant toxicity in HNSCC tumor cells only in combination with RT. Noticeably, inhibition of ATR via VE-822 + RT treatment shows greater immune modulating potential regarding surface markers on tumor cells, release of IL-6 and slight upregulation of activation markers on NK cells after co-culture. This work was supported by the IZKF Erlangen and by the DFG (GRK2599)."

IO biomarker • Tumor cell • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ANXA5 • CD14 • CD36 • ICOS • IL6 • NCR1 • NKG2D

Potentiating the radiation-induced type I interferon anti-tumoral immune response by ATM inhibition in pancreatic cancer. (PubMed, JCI Insight) - "We evaluated the effects of AZD1390 or a structurally related compound AZD0156 on innate immune signaling and found that both inhibitors enhanced radiation-induced T1IFN expression via the POLIII/RIG-I/MAVS pathway. Adaptive immune responses to combination therapy provided systemic control of contralateral tumors outside of the radiation field. Taken together, we show that a clinical candidate ATM inhibitor enhances radiation-induced T1IFN leading to both innate and subsequent adaptive anti-tumoral immune responses and sensitization of otherwise resistant pancreatic cancer to immunotherapy."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD8

Identification of Novel, Selective Ataxia-Telangiectasia Mutated Kinase Inhibitors with the Ability to Penetrate the Blood-Brain Barrier: The Discovery of AZD1390. (PubMed, J Med Chem) - "Starting from clinical candidate AZD0156, 4, we investigated the imidazoquinolin-2-one scaffold with the goal of improving likely CNS exposure in humans. These studies identified compound 24 (AZD1390) as an exceptionally potent and selective inhibitor of ATM with a good preclinical pharmacokinetic profile. 24 showed an absence of human transporter efflux in MDCKII-MDR1-BCRP studies (efflux ratio <2), significant BBB penetrance in nonhuman primate PET studies (K 0.33) and was deemed suitable for development as a clinical candidate to explore the radiosensitizing effects of ATM in intracranial malignancies."

Journal • Ataxia • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • ABCB1

Antioxidants and azd0156 Rescue Inflammatory Response in Autophagy-Impaired Macrophages. (PubMed, Int J Mol Sci) - "Importantly, the chemical activation of autophagy or ATM inhibition during M1 polarization reduced the M1 phenotype and inflammation, whereas inhibiting autophagy during M2 polarization also reduced the M2 phenotype. Thus, our findings highlight the importance of the autophagy-ATM pathway in driving macrophage inflammation."

Journal • Ataxia • Atherosclerosis • Cardiovascular • Dyslipidemia • Immunology • Inflammation • Inflammatory Arthritis • Movement Disorders • Primary Immunodeficiency • Rheumatoid Arthritis • Rheumatology • ATG16L1 • GLI2 • IL18 • RELA

Mixed effects modeling of radiotherapy in combination with immune checkpoint blockade or inhibitors of the DNA damage response pathway. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Model fit results indicated AZD0156 to be a more potent DDRi than olaparib. Simulations of alternative doses indicated that reducing efficacy of anti-PD-L1 by 68% would potentially provide evidence for a benefit of ATM inhibition in combination with ICB and increase the relative efficacy of tri-therapy."

Checkpoint block • Checkpoint inhibition • Combination therapy • IO biomarker • Journal • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency

ATM inhibition augments type I interferon response and antitumor T-cell immunity when combined with radiation therapy in murine tumor models. (PubMed, J Immunother Cancer) - "Combined radiation and AZD0156 increase STING-dependent antitumor response. Tumor-derived cell-autonomous IFN-β amplification drives both MHC-I and PD-L1 induction at the tumor cell surface, which is required by anti-PD-L1 therapy to promote antitumor immune response following RT and AZD0156 combination therapy."

IO biomarker • Journal • Preclinical • Ataxia • Head and Neck Cancer • Immunology • Melanoma • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • IFNAR1 • IFNAR2 • IFNB1 • STING

ATM inhibition augments type I interferon response and antitumor T-cell immunity when combined with radiation therapy in murine tumor models (J Immunother Cancer) - "Combining RT and AZD0156 reduced tumor growth compared with RT or AZD0156 alone in mice bearing MOC2 or B78 tumors. Low-dose AZD0156 (1–100 nM) alone did not affect tumor cell proliferation but suppressed tumor cell clonogenicity in combination with RT. Low-dose AZD0156 with RT synergistically increased IFN-β, major histocompatibility complex (MHC)-I, and programmed death-ligand 1 (PD-L1) expression in tumor cells. In contrast to wild-type mice, IFNAR1-KO mice showed reduced CD8+T cell tumor infiltration and poor survival following RT+AZD0156 treatment."

Preclinical • Oncology • Solid Tumor

Simultaneous Delivery of Dual Inhibitors of DNA Damage Repair Sensitizes Pancreatic Cancer Response to Irreversible Electroporation. (PubMed, ACS Nano) - "Using reactive oxygen species-sensitive polymeric micelles coloaded with Olaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), and AZD0156, an inhibitor of ataxia telangiectasia mutated (ATM), the resultant nanoformulation (M-TK-OA) disrupted both homologous recombination and nonhomologous end joining signaling of the DDR response and impaired colony formation in pancreatic cancer cells after RE. The efficacy of combined IRE and M-TK-OA treatments was partially attributed to the activation of cyclic GMP-AMP synthase-stimulator of interferon genes innate immune responses. Our study suggests that dual inhibition of PARP and ATM with nanomedicine is a promising strategy to enhance the pancreatic cancer response to IRE."

Journal • Ataxia • Gastrointestinal Cancer • Hepatology • Immunology • Movement Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Primary Immunodeficiency • Solid Tumor • CD8 • CGAS • STING

Genome-wide CRISPR/Cas9 library screening identified ATM signaling network genes as critical drivers for resistance to ATR inhibition in soft-tissue sarcomas: synthetic lethality and therapeutic implications. (PubMed, Exp Hematol Oncol) - "Moreover, the combination of AZD6738 and AZD0156 induced significantly higher levels of DNA damage than either drug used as single agent alone. In summary, our results demonstrate that targeting ATM is an effective approach to overcome resistance to ATR inhibition in different STS subtypes, including the most frequent histologies."

Journal • Synthetic lethality • Leiomyosarcoma • Liposarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Undifferentiated Pleomorphic Sarcoma

Targeting DNA polymerase theta and ATM leads to synergistic killing of mantle cell lymphoma cells (AACR 2023) - "In vitro, single-agent treatment with novobiocin or ART558 caused a significant cytotoxic effect at physiologically relevant concentrations in ATM-deficient cells and co-treatment of novobiocin or ART558 with AZD0156 was synergistic in killing ATM-proficient MCL cells. Importantly, POLQ inhibitors significantly decreased the cell viability of MCIR1, which is an ibrutinib-resistant MCL cell line... POLQ is a promising target in MCL, especially in ATM-deficient setting. In ATM-proficient MCL, targeting ATM and POLQ is synergistic. Our data has the potential to uncover novel biomarker-driven drug therapy of POLQ inhibitors in R/R MCL."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • POLQ

Phosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target in B cell acute lymphoblastic leukemia. (PubMed, Sci Transl Med) - "The combination of AZD0156 with staurosporine or vincristine exhibits a synergistic effect on inhibition of refractory/relapsed B-ALL cell survival and leukemia progression in PDX models. Collectively, our study reveals an oncogenic role of the phosphorylated TET1 protein in B-ALL independent of its catalytic activity and highlights the therapeutic potential of targeting TET1 signaling for the treatment of refractory/relapsed B-ALL."

Journal • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • PRKCE • STAT5B • TET1

The effect of the ATM inhibitor AZD0156 on the radiosensitivity of human breast cancer and lung fibroblast cells. (PubMed, J Cancer Res Ther) - "No efficacy was detected on cell cycle analysis, and clonogenic survival was not significantly decreased in WI-38 cells. The combination use of irradiation and AZD0156 has improved efficacy of tumor cell-specific cell cycle arrest and decreasing clonogenic survival."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER