AZD7648 / AstraZeneca - LARVOL DELTA

Inhibition of ATM, ATR and DNA-PK radiosensitises 3D uveal melanoma models to X-rays and proton beam therapy. (PubMed, Front Oncol) - "Here, we investigate the response of 3D spheroid models of UM to both X-rays and PBT in the presence of inhibitors of ATM (AZD1390), ATR (AZD6738) and DNA-PK (AZD7648). We demonstrate that inhibition of these protein kinases significantly suppresses the growth of UM spheroids exposed to both X-rays and PBT, which is primarily driven by delayed and persistent DSBs, leading to the accumulation of chromosomal aberrations. These results highlight the potential of combining ATM, ATR or DNA-PK inhibitors to enhance radiotherapy efficacy, and particularly with targeted PBT, to help improve clinical outcomes in UM."

Journal • Ataxia • Eye Cancer • Immunology • Melanoma • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Uveal Melanoma • ATR

Simultaneous inhibition of DNA-PKcs and 53BP1 enables enrichment-free replacement of the CFTR cDNA in airway stem cells (NACFC 2026) - "Overall, combined inhibition of DNA-PKcs with AZD7648 and53BP1 with HEP enables efficient CFTR cDNA insertion in the native CFTRlocus in ABCs and iPSCs. Thus, it lays the foundation for the further development of autologous genome edited stem cell therapies using ABCs and iPSCsto treat multisystem disease in CF."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • KRT5 • POLQ • TINCR • TP53BP1 • TP63

Let's not jump to conclusions: split template jumping prime editing of CFTR exon 12 utilizing Cas12a (NACFC 2026) - "To evaluate TJ-PE, cells were transfected with both gRNAs, Cas12a, the RT-MCP, and the petRNA in the presence or absence of AZD7648 (a DNA-PK inhibitor which limits Nonhomologous End Joining (NHEJ))... We have shown that TJ-PE utilizing Cas12a can rewrite CFTR Exon 12 in human cells with 22-fold greater efficiency than a Cas9-based system. Future studies will focus on the use of improving editing efficiency using modifiers of DNA repair pathways."

Sequential CD2/CD3/CD28 activation improves nonviral large-payload chimeric antigen receptor knock-in at the T cell receptor α constant locus. (PubMed, Cytotherapy) - "Here, we show that sequential CD2/CD3/CD28 activation improves HDR-mediated large-payload knock-in at the T cell receptor α constant (TRAC) locus and increases viable CAR-T cell yield under an AZD7648-supported nonviral editing framework...Functionally, engineered nonviral TRAC-CD19.CAR-T cells exhibit antigen-specific cytotoxicity in vitro and suppress leukemia progression in an NSG xenograft model, with antitumor activity that approached that of a lentiviral CAR-T reference in this proof-of-function xenograft model. This work establishes an optimized sequential activation strategy to improve nonviral, large-payload TRAC-targeted CAR-T cell engineering and may inform future development of precision cellular immunotherapy manufacturing workflows."

Journal • Hematological Malignancies • Leukemia • Oncology • CD2

Dataset of RNA-seq profiles from THP-1-derived macrophages pretreated with AZD7648 and stimulated with CT DNA. (PubMed, Data Brief) - "Clean reads ranged from 54.83 to 70.25 million per sample, with Q30 values of 97.18%-97.34%, total mapping rates of 98.24%-98.51%, and unique mapping rates of 95.55%-95.81%. This dataset provides a resource for comparative transcriptomic analyses of cytosolic DNA stimulation and DNA-PKcs inhibition in macrophage cells and may support reuse in studies of innate immune signaling, cytosolic DNA sensing, and pathway-focused reanalysis."

Circulating tumor DNA • Journal

Targeting DNA-PK: medicinal chemistry insights into small-molecule inhibitor discovery and optimisation. (PubMed, RSC Med Chem) - "Representative scaffolds, including chromen-4-one derivatives and next-generation clinical candidates such as AZD7648 and VX-984, are discussed. Finally, we summarise current clinical progress in early phase trials and remaining challenges, including achieving tolerability and efficacy when compounds are administered both as a single agent, or in combination. Taken together, this review highlights both the therapeutic potential of DNA-PK-targeting inhibition and the challenges encountered in clinical development, providing a framework to guide future strategies for DNA-PK-targeted therapeutics."

Journal • Review • Oncology

Radiosensitisation of Head and Neck Cancer Cells to Protons of Increasing LET Through Targeting DNA Double Strand Break Repair. (PubMed, Cells) - "We demonstrate that inhibitors against ATR (AZD6738), and particularly ATM (AZD1390) and DNA-Pkcs (AZD7648), could significantly decrease clonogenic survival of HNSCC cell lines following PBT at both low and relatively high LET (~2 keV/µm and ~8 keV/µm, respectively). We confirmed that the inhibitors in combination with PBT led to DSB persistence through neutral comet assays and monitoring γH2AX/53BP1 foci. We also show that this strategy can enhance the sensitivity of patient-derived organoids of HNSCC to PBT of both low and high LET, highlighting this as a strategy which should be exploited further."

Journal • Ataxia • Head and Neck Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ATR • TP53BP1

Simultaneous inhibition of DNA-PKcs and 53BP1 enables highly efficient Cas9-mediated insertion of genes up to 7 kb in primary cells (ASGCT 2026) - "We screened previously reported compounds that inhibit DNA-PKcs in NHEJ (AZD7648), polymerase theta in MMEJ (PolQi2), and other DNA repair pathway proteins including 53BP1 (HEP), ATR (VE822), and checkpoint kinases (AZD7762). Statistical significance determined using one-way ANOVA followed by Tukey's. ***p<0.001."

Genetic Disorders • CFTR • NOS3 • TP53BP1

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

Strategies to Improve CRISPR–Cas9–Mediated Whole-Gene Knock-In and Integrity Assessment (ASGCT 2026) - "NHEJ and MMEJ were inhibited using AZD7648 (0.5 µM) and PolQi2 (3 µM)...Figure 2. Genomic aberration analysis via PCR-based and PCR-free nanopore sequencing.(a) PCR-based long-read and PCR-free adaptive sampling workflows.(b) Adaptive sampling coverage across regions flanking the cut site and CFTR cDNA.(c) Summary of editing outcomes from adaptive sampling.(d) Gel confirming edited and unedited amplicon sizes with two primer sets.(e) Insertion efficiency by both sequencing methods, benchmarked by ddPCR."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR • KRT5 • TP63

Non-viral knock-in of long HDR donors in hematopoietic stem and progenitor cells using circular single-stranded DNA for CDAII gene therapy (ASGCT 2026) - "The incorporation of HDR enhancers, such as M3814 and AZD7648 (DNA-PK inhibitors) and XL413 (CDC7 inhibitor), nearly doubled the knock-in efficiency for both donor types. Conclusion These results demonstrate that the cssDNA platform is a feasible system for the knock-in of long HDR donors in engraftable HSPCs. Our study establishes cssDNA as a promising non-viral HDR donor format for targeted gene therapy of CDAII and other hematopoietic disorders, paving the way for safer HDR strategies in HSPCs."

Gene therapy • IO biomarker • Bone Marrow Transplantation • Gene Therapies • Hematological Disorders • CD34 • CD38 • CDC7 • SEC23B • THY1

Optimized conditions for high efficiency CRISPR-mediated HDR with reduced genomic aberrations (ASGCT 2026) - "Separately, while inhibitors of non-homologous end joining (NHEJ) such as AZD-7648 are commonly used to significantly increase editing rates (Selvaraj et al., Nature Biotechnology 2024), there is evidence that inhibiting NHEJ can increase the frequency of genomic aberrations such as chromosomal translocations and large deletions (Cullot et al., Nature Biotechnology 2024)...Conclusion Optimal HDR editing conditions should maximize editing efficiency while minimizing off- target effects, chromosomal aberrations and cellular toxicities. Our results demonstrate that this can be achieved using an AAV repair template in combination with i53 and PolQi2, providing a framework for safer and more effective HDR-engineered cellular therapies."

CD34 • TP53BP1

DNA-PKcs inhibitor AZD7648 reveals sgRNA cross-contaminants and enhanced sensitivity of genome engineering off-target activity in HSPCs (ASGCT 2026) - "Conclusion Collectively, these findings highlight the critical role of NHEJ in preserving genomic stability and underscore the need for high-sensitivity genotoxicity profiling when developing genome-editing strategies for clinical translation. Figure Legend Graphical Abstract; Schematic overview of three complementary techniques used to quantify genomic aberrations in human HSPCs following DNA-PKcs-modulated genome editing, including sgRNA contamination-driven off-target events."

Prime assembly enables targeted DNA integration with high genome-wide specificity in human cells (ASGCT 2026) - "Where indicated, Jurkat cells were treated with 0.5 µM AZD7648 and 0.5 µM PolQi1 for three days post-nucleofection...Each plot represents the total number of deduplicated UMI reads from three independent biological replicates. OT, off-target."

CD34 • IL2RG • TINF2

PRKDC Inhibition as a Novel Radiosensitization Strategy in Advanced Prostate Cancer through NHEJ-Targeted Synthetic Lethality (AUA 2026) - "Furthermore, combination therapy using the PRKDC inhibitor AZD7648 and the PARP inhibitor Olaparib demonstrated a potent synergistic effect. PRKDC inhibition is a promising radiosensitization strategy for NEPC. The combination of AZD7648 and radiotherapy significantly improved survival in preclinical models, warranting further clinical investigation."

Metastases • Synthetic lethality • Genito-urinary Cancer • Genitourinary Neuroendocrine Carcinoma • Oncology • Prostate Cancer • Solid Tumor • PRKDC

Synergistic Effects of DNA-PKcs Inhibition and Radiotherapy in Esophageal Squamous Cell Carcinoma. (PubMed, FASEB J) - "In vitro, ESCC cell lines (TE13 and Eca9706) were co-treated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitors (AZD7648 or NU7741) or PRKDC-targeting siRNA plus irradiation...Our study reveals a novel mechanism by which DNA-PKcs inhibition augments radiosensitivity in ESCC. Targeting DNA-PKcs could represent a promising strategy to improve the efficacy of radiotherapy in ESCC, offering a potential therapeutic approach to overcome radioresistance."

Journal • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • CASP3 • CDK1 • CHEK1 • CHEK2 • PRKDC

DNA-PKcs inhibitor AZD7648 reveals sgRNA cross-contaminants and enhanced sensitivity of genome engineering off-target activity in HSPCs. (PubMed, Nucleic Acids Res) - "A modified, translocation-quantitative rhAmpSeq reports all translocation combinations between two loci, enabling robust off-target validation beyond indel-only readouts. Finally, we evaluate AZD7648, finding limited aberration increases with precise nucleases and reconciling reports of extensive large deletions by quantifying assay- and design-dependent biases."

Journal • Tumor mutational burden • TMB

DNA-PKcs regulates type I interferon responses in macrophages during bacterial infection (IMMUNOLOGY 2026) - "We also compared the transcriptomes of activated macrophages that were treated with a small molecule inhibitor of DNA-PKcs, AZD7648, relative to vehicle-only controls... Taken together, these data suggest a potential role for DNA-PKcs in modulating ISG expression beyond its regulation of type I interferon production."

Late-breaking abstract • Infectious Disease • STING

Highly efficient and scarless genome editing via essential gene-coupled homology-directed repair. (PubMed, Genome Res) - "ESS-HDR also outperforms chemical enhancers including RS-1, SCR7, nocodazole, and AZD7648. Together, these findings establish ESS-HDR as a broadly applicable strategy for efficient, scarless genome editing without external selection markers."

Journal • LMNB1 • TUBA1B

Early biomarker dynamics are associated with treatment efficacy in a preclinical model of radiotherapy combined with a DNA damage response agent (AACR 2025) - "In summary, both in vitro assays and in vivo models have been developed to explore the synergistic effects of combining radiotherapy with DDR agents. The combination of radiotherapy with the AZD7648 inhibitor resulted in delayed tumor growth in vivo. Early changes in protein and gene biomarkers were consistent with target engagement and treatment efficacy."

Preclinical • Lung Cancer • Oncology • Solid Tumor

Novel non-homologous end-joining inhibitor AZD7648 and PARP inhibitor olaparib show synergistic activity in GFI1-36N-MLL-AF9 leukemic cells (DKK 2026) - "Independently of this, PARPi trials are under investigation of AML. In this study, we therefore investigate the effect of blocking non-homologous end-joining (NHEJ) using the novel DNAPK"

Acute Myelogenous Leukemia • Leukemia • GFI1

PRKDC inhibition as a novel radiosensitization strategy in advanced prostate cancer through NHEJ-targeted synthetic lethality (ENETS 2026) - "Olaparib demonstrated a potent synergistic effect. PRKDC inhibition is a promising radiosensitization strategy for NEPC. The combination of AZD7648 and radiothera - py significantly improved survival in preclinical models, warran - ting further clinical investigation."

Metastases • Synthetic lethality • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • PRKDC

Discovery of Novel Heterotetracyclic DNA-Dependent Protein Kinase (DNA-PK) Inhibitors with Improved Oral Bioavailability and Potent Cancer Immunotherapy-Potentiating Activity. (PubMed, J Med Chem) - "Remarkably, D11 exhibited excellent pharmacokinetics in SD rats (oral bioavailability: 42.6%; half-life: 50 h) and outperformed the clinical candidate AZD-7648 in LoVo xenografts (TGI = 72.9% vs 54.6% at 50 mg/kg, p.o.). It also synergized with anti-PD-L1 mAb to enhance CD8+ T-cell infiltration. Overall, D11 is a promising heterotetracyclic DNA-PK inhibitor with superior in vivo efficacy, favorable pharmacokinetics, and immunomodulatory potential, supporting further development."

Journal • Oncology • CD8

Single-cell multiplex approaches deeply map ON-target CRISPR-genotoxicity and reveal its mitigation by palbociclib and long-term engraftment. (PubMed, Nat Commun) - "Conversely, short-term risk is significantly increased with DNA-PKcs inhibitor AZD7648. Fortunately, targeting HBG1/2p, scSNP-DNA-seq reveals that ON-target genotoxic events are no longer detectable after long-term xenografts. This work demonstrates that scSNP-DNA-seq should be routinely implemented to monitor chromosomal rearrangements before and after CRISPR-edited cell infusions."

Journal • Gene Therapies

Targeting hells‑mediated chromatin accessibility to sensitize ALK‑negative anaplastic large cell lymphoma to JAK/STAT and DNA‑PK inhibition (ASH 2025) - "In several ALCL cell lines, HELLS depletionsynergized with an IC20 dose of Ruxolitinib (a JAK inhibitor) or AZD7648 (a DNA-PK inhibitor), resulting insignificant synthetic lethality compared to single-agent treatment or control cells.In conclusion, this study demonstrates that HELLS drives the expression of immune-related genesthrough chromatin remodeling in aggressive ALK- ALCL. Its inhibition uncovers combinatorialvulnerabilities, providing a rationale for dual-targeted therapies involving JAK/STAT or DNA-PK pathwayinhibition."

Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • T Cell Non-Hodgkin Lymphoma • ALK • HELLS