AZD1390 / AstraZeneca - LARVOL DELTA

Role of DNA damage sensing and TP53 function as modulators of sensitivity to calicheamicin-based antibody-drug conjugates (ADCs) for acute leukemia (ASH 2025) - "Better survival of some patients with the CD33 ADC, gemtuzumab ozogamicin (GO), and the CD22 ADC, inotuzumab ozogamicin (InO), validate these efforts, but these ADCs are ineffective in many others...CLM-induced cytotoxicity was assessed in vitro in the presence/absence of a Mouse Double Minute 2 homolog (MDM2) inhibitor (idasanutlin), Ataxia-Telangiectasia Mutated (ATM) inhibitor (AZD1390, lartesertib), Ataxia Telangiectasia and Rad3-related (ATR) inhibitor (ceralasertib), Checkpoint Kinase 1 and Checkpoint Kinase 1 (Chk1/Chk2) inhibitors (prexasertib, BML-277), and poly(ADP-ribose) polymerase (PARP) inhibitor (veliparib)... Our studies identify ATM, MDM2, and TP53 as key modulators of CLM-induced cytotoxicity in acute leukemia cells. These results support further evaluation of combination therapies with corresponding small molecule inhibitors (currently pursued in patients with other cancers) toward possible clinical testing as novel strategies to increase the efficacy..."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Ataxia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Immunology • Leukemia • Movement Disorders • Primary Immunodeficiency • CD22 • CD33 • CDKN1A • FBXW7 • TP53

ATM/DNA-PK Inhibitor XRD-0394 Enhances Radiation-Induced Pro-Inflammatory Responses in Glioma Models (SNO 2025) - "We previously evaluated the radiosensitizing effect of the ATM inhibitor AZD1390 in both p53-mutant and wild-type DMGs and observed enhanced sensitivity in p53-mutant models (Mangoli et al., in press). In conclusion, a dual inhibitor of ATM and DNA-PK enhances radiation-induced cytotoxicity and pro-inflammatory signaling in GBM and DMG models. Ongoing studies will further define the therapeutic potential of this combination strategy."

IO biomarker • Ataxia • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • High Grade Glioma • Immunology • Inflammation • Movement Disorders • Primary Immunodeficiency • Solid Tumor • CCR4 • STING

IDENTIFICATION OF A DNA REPAIR INHIBITOR FOR THE COMBINATION WITH LURBINECTEDIN AND RADIOTHERAPY IN SARCOMA CELL LINES (CTOS 2025) - "Objective: Improved multimodal treatment could optimize therapeutic outcomes for sarcoma patients. Our preclinical data suggest that the combination of LU with RT has no sensitizing effect compared to LU treatment alone in sarcoma cell lines. However, combining LU and IR with DNA repair inhibitors such as the ATRi VE-822 is a promising way to improve sarcoma treatment."

Preclinical • Fibrosarcoma • Liposarcoma • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • Synovial Sarcoma • ANXA5

ATM/DNA-PK Inhibitor XRD-0394 Enhances Radiation-Induced Pro-Inflammatory Responses in Glioma Models (WFNOS 2025) - "We previously evaluated the radiosensitizing effect of the ATM inhibitor AZD1390 in both p53-mutant and wild-type DMGs and observed enhanced sensitivity in p53-mutant models (Mangoli et al., in press). In conclusion, a dual inhibitor of ATM and DNA-PK enhances radiation-induced cytotoxicity and pro-inflammatory signaling in GBM and DMG models. Ongoing studies will further define the therapeutic potential of this combination strategy."

IO biomarker • Ataxia • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Immunology • Inflammation • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • CCR4 • STING

YL0712-3, a Novel ATR/ATM Inhibitor, Demonstrates Anti-Tumor Activity in TP53 Mutant DLBCL through Synthetic Lethality and Degradation of Mutant p53 (ASH 2024) - "The in vitro activity of YL0712-3 was assessed across various TP53 mutant and wild-type DLBCL cell lines, with ATR inhibitor Elimusertib and ATM inhibitor AZD1390 as positive controls. Conclusion : The ATR/ATM inhibitor YL0712-3 effectively targets TP53 mutant DLBCL cells by inhibiting the ATM/Chk2 and ATR/Chk1 pathways and inducing proteasome-mediated degradation of mutant p53 protein. YL0712-3 exhibits promising anti-tumor activity in both in vitro and in vivo models, especially when combined with R-CHOP, presenting a potential therapeutic strategy for TP53 mutant DLBCL."

Synthetic lethality • Ataxia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immunology • Lymphoma • Movement Disorders • Non-Hodgkin’s Lymphoma • Oncology • Primary Immunodeficiency • Targeted Protein Degradation • CHEK2

ATM/DNA-PK Inhibitor XRD-0394 Enhances Radiation-Induced Pro-Inflammatory Responses in Glioma Models (WFNOS 2025) - "We previously evaluated the radiosensitizing effect of the ATM inhibitor AZD1390 in both p53-mutant and wild-type DMGs and observed enhanced sensitivity in p53-mutant models (Mangoli et al., in press). In conclusion, a dual inhibitor of ATM and DNA-PK enhances radiation-induced cytotoxicity and pro-inflammatory signaling in GBM and DMG models. Ongoing studies will further define the therapeutic potential of this combination strategy."

IO biomarker • Ataxia • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • High Grade Glioma • Immunology • Inflammation • Movement Disorders • Primary Immunodeficiency • Solid Tumor • CCR4 • STING

AZD1390: Data from P1 trial (NCT03423628) for brain metastases and newly diagnosed glioblastoma in H2 2026 (AstraZeneca) - Q3 2025 Results

P1 data • Glioblastoma • Oncology

Inhibition of ATM and xCT Enhances Radiation Sensitivity and Suppresses Tumor Growth in Glioblastoma (ASTRO 2025) - "Irradiation was specifically administered to brain with 2 Gy per day for five consecutive days, with or without ATM inhibitors (AZD0156, AZD1390, 1 mg/kg) and the xCT inhibitor sulfasalazine (100 mg/kg). Our study demonstrated that the simultaneous inhibition of ATM and xCT significantly enhanced the radiosensitivity of GBM both in vitro and in vivo. Furthermore, GBM tumor growth was markedly suppressed with this approach. These findings suggest that radiotherapy combined with ATM and xCT inhibition may serve as a promising strategy for overcoming radioresistance in GBM and improving therapeutic outcomes."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Quantitative Imaging of ATM: PET and Autoradiography Studies Using [11C]AZD1390. (PubMed, ACS Chem Neurosci) - "The binding parameters [Kd (0.23 nM), Ki (0.58 nM), and Bmax (267.0 fmol/mg tissue)] demonstrate the high affinity of [11C]AZD1390 and imply that ATM is present at levels (Bmax) sufficient for reliable quantification in the brain. While AZD1390 may not be ideal for accurately measuring ATM concentrations due to saturable efflux or other dose nonlinearity mechanisms, these findings support the overall feasibility of quantifying ATM in vivo using PET imaging."

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

ATM inhibition increases the anti-tumor efficacy of radium-223 (Ra-223) against prostate cancer bone metastasis in preclinical models. (PubMed, JBMR Plus) - "Radiosensitization with either the ATMi AZD0156 or AZD1390 prior to 300 kBq/kg Ra-223 treatment further reduced bone metastasis by 94.1% and 88.7%, respectively, whereas combining AZD1390 with 50 kBq/kg synergistically reduced tumor size and the number of mice with tumors in bone by 50% compared with Ra-223 alone. Instead, this treatment combination increased subsets of anti-tumor immune cells. Taken together, our data suggest that ATMi may be an effective radiosensitizer for increasing efficacy of Ra-223 in prostate cancer bone metastases, reducing Ra-223-induced adverse effects on bone."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Osteosarcoma • Prostate Cancer • Solid Tumor

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

GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (clinicaltrials.gov) - P2/3 | N=1280 | Recruiting | Sponsor: Global Coalition for Adaptive Research | Trial completion date: Jun 2028 ➔ Jun 2030 | Trial primary completion date: Jun 2026 ➔ Jun 2028

Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Hematological Disorders • Oncology • Solid Tumor

AZD1390: Data from P1 trial (NCT03423628) for brain metastases and newly diagnosed glioblastoma in H1 2026 (AstraZeneca) - H1 & Q2 2025 Results

P1 data • Glioblastoma • Oncology

DNA Damage Response Regulation Alleviates Neuroinflammation in a Mouse Model of α-Synucleinopathy. (PubMed, Biomolecules) - "In this study, we evaluated the therapeutic potential of AZD1390, a highly selective and brain-penetrant ATM inhibitor, in reducing neuroinflammation and improving behavioral outcomes in a mouse model of α-synucleinopathy...Overall, these results suggest that targeting the DDR via ATM inhibition reduces genotoxic stress, suppresses neuroinflammation, and improves behavioral outcomes in a mouse model of α-synucleinopathy. These findings underscore the therapeutic potential of DDR modulation in PD and related synucleinopathy."

Journal • Preclinical • Ataxia • CNS Disorders • Immunology • Inflammation • Movement Disorders • Parkinson's Disease • Primary Immunodeficiency • CDKN1A

Achieving human brain exposure with the oral ataxia-telangiectasia mutated kinase inhibitor AZD1390, a substrate of aldehyde oxidase. (PubMed, Drug Metab Dispos) - "This case example demonstrates that despite the lack of relevant translational pharmacokinetics information from animals, via careful human in vitro benchmarking, certain AO substrates with suitable properties can be progressed and generate acceptable oral clinical pharmacokinetics. AZD1390 is a successful case example of prosecuting an AO substrate in the clinic after many documented failures."

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

Combinatorial assessment of DXd-based antibody drug conjugates with DNA damage response inhibitors in ovarian and endometrial cancers (EACR 2025) - "Our findings indicate that combining Dato-DXd and T-DXd with specific DDR inhibitors potentially enhances anti-tumour activity in ovarian and endometrial cancer models, which offers potential pathways for clinical translation. These combinations, particularly those involving ATM and ATR inhibitors, support the need for further investigation in clinical settings."

Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor • HER-2 • TACSTD2

Preclinical Evaluation of T-DXd and AZD1390 in HER2-Low, Triple-Negative Breast Cancer Models (EACR 2025) - "T-DXd plus AZD1390 shows significant synergy in growth reduction of cancer cells in 2D and 3D culture conditions, even at low nanomolar concentrations. This combination shows promising results to enhance target therapies for TNBC patients."

Preclinical • Ataxia • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Triple Negative Breast Cancer • CASP3 • CASP7 • HER-2 • TOP1

Restoring RAI Sensitivity via ATM Inhibition and Genotoxic Stress (SNMMI 2025) - "In vitro and in vivo models evaluated the synergistic effects of combining ATM inhibitors (AZD1390) with RAI therapy... Single-cell analysis revealed a progressive increase in ATM expression during thyroid cancer progression, with the highest levels observed in anaplastic thyroid carcinoma (ATC) and RAI-R PTC. Immunohistochemistry confirmed elevated ATM expression in RAI-R patient samples compared to RAI-sensitive counterparts. Mechanistically, RAI-induced DNA damage primarily resulted in AP site accumulation rather than double-strand breaks (DSBs)."

Ataxia • Endocrine Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma

Global Coalition for Adaptive Research Announces Initiation of AZD1390 in GBM AGILE Trial (GlobeNewswire) - "The Global Coalition for Adaptive Research (GCAR) today announced the activation of AstraZeneca's AZD1390 in GBM AGILE...the world's first global adaptive platform trial for glioblastoma. The AZD1390 arm will be evaluated for the treatment of adult patients with newly diagnosed glioblastoma."

Trial status • Glioblastoma

Testing the Addition of an Anti-Cancer Drug, AZD1390, During Radiation Therapy for Newly Diagnosed High Grade Glioma, Diffuse Midline Glioma, or Diffuse Intrinsic Pontine Glioma (clinicaltrials.gov) - P1 | N=54 | Recruiting | Sponsor: Children's Oncology Group | Not yet recruiting ➔ Recruiting | Initiation date: May 2025 ➔ Feb 2026

Enrollment open • Trial initiation date • Astrocytoma • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioblastoma • Glioma • Malignant Glioma • Oncology • Pediatrics • Solid Tumor

DNA damage response inhibitors enhance interferon signaling in an LET-dependent manner after irradiation of glioblastoma cells (ESTRO 2025) - "Material/ Human glioblastoma U-251 and T98G cells were irradiated with X-rays (LET: ~4 keV/mm; 2-30 Gy), protons (LET: 4.8 and 41.9 keV/mm; 2-6 Gy) and carbon ions (LET: 28 and 73 keV/mm; 1-4 Gy), with and without ATR inhibitor (VE-822 at 50-250nM) or ATM inhibitor (AZD1390 at 10nM). These findings indicate that DNA damage response inhibitors can enhance IFN signaling following X-, proton and carbon ion irradiation, with a strong positive dependency on LET. DNA damage response inhibitors may potentially be used in combination with proton or carbon ion therapy to enhance tumor cell radiosensitivity and boost antitumor immune responses."

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

Enhancing antitumor immunity by targeting cancer associated fibroblasts with radiation and ATM inhibition (ESTRO 2025) - "Cells were treated with radiation (2, 6 or 18 Gy) and inhibitors targeting ATR (VE-822), ATM (AZD1390), CHK1 (LY2606368) and WEE1 (AZD1775). This study demonstrates that combining radiation with ATM inhibition can effectively target CAFs, inducing an IFN-I response. Beyond the well-established radiosensitizing effects of ATM inhibition, our findings reveal a potential novel role for ATM inhibitors in reprogramming NSCLC-CAFs into an immune-activating phenotype. This dual mechanism represents a promising approach to enhance radiotherapy-immunotherapy synergies by reducing the immunosuppressive influences of the tumor microenvironment."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CAFs • CDKN1A • CHEK1 • IFNB1

ATM inhibition with AZD1390 and conventional radiotherapy in non-small cell lung cancer: interim report from the CONCORDE phase Ib trial (NCT04550104) (ESTRO 2025) - P1 | "Oesophagitis duration was prolonged (median 67 days, range 8-181), and 7 participants required morphine (50%). AZD1390 was escalated to dose level 3 (40mg once-daily on RT days). Based on the observed oesophageal toxicity, the independent Safety Review Committee decided to close Arm B early. Analysis of patient-reported outcomes, efficacy outcomes and oesophagus-derived cfDNA are ongoing."

P1 data • Ataxia • Brain Cancer • CNS Tumor • Gastrointestinal Disorder • Glioblastoma • Immunology • Lung Cancer • Movement Disorders • Non Small Cell Lung Cancer • Oncology • Primary Immunodeficiency • Solid Tumor • Squamous Cell Carcinoma

ATM inhibitor AZD1390 sensitizes nasopharyngeal cancer cells to chemotherapy by reversing chemotherapy-induced autophagy (AACR 2025) - "Our findings demonstrated that AZD1390 augments the sensitivity of NPC cell lines to chemotherapy through the reversion of chemotherapy-induced autophagy. Therefore, AZD1390 could potentially serve as a chemosensitizer in NPC treatment."

Head and Neck Cancer • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • ANXA5

Radiosensitization via ATM inhibition in small cell lung cancer leads to increased immunogenicity and tumor infiltration (AACR 2025) - "Evaluation of ATM inhibition (ATMi) in combination with IR increases tumour T cell immunogenicity through a cGAS-STING-mediated mechanism.Methods and Materials: We investigated the combination of ATMi (AZD1390) and IR in SCLC cell-lines SBC5 and SHP77, to determine the synergism of cGAS-STING activation via immunofluorescence... In this study, we demonstrated pharmacological inhibition of ATM enhanced SCLC chemokine expression in a cGAS-STING-dependent manner. We further validated this phenotype in a syngeneic SCLC murine model. Despite this marked improvement in SCLC T cell infiltration no further benefits was observed."

IO biomarker • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CGAS • CXCL10 • PTPRC • STING