AZD7648 / AstraZeneca - LARVOL DELTA

DNA-PKcs inhibitor AZD7648 reveals sgRNA cross-contaminants and enhanced sensitivity of genome engineering off-target activity in HSPCs (ASGCT 2026) - No abstract available

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

POLQ and DNA-PK inhibition in muscle-invasive bladder cancer : Enhancing radiosensitivity with novel DNA damage response inhibitors to improve radiotherapy outcomes. (PubMed, Pathologie (Heidelb)) - "DNA-PKi radiosensitized MIBC cells more effectively than POLQi, particularly SCC. DNA damage response (DDR) inhibitors thus have therapeutic potential in MIBC, depending on the target protein and tumor subtype."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Urothelial Cancer • POLQ

Harnessing DNA barcoding to enhance and sustain polyclonality in gene-edited hematopoietic stem cells. (PubMed, Mol Ther Methods Clin Dev) - "NHEJ inhibitor AZD-7648, significantly boosted editing efficiency in vitro, and a shorter transduction period enhanced engraftment and clonal balance without compromising editing outcomes. This refined strategy for gene editing in human HSPCs optimizes both efficiency and long-term polyclonal dynamics and has important implications for clinical applications."

Journal • Hematological Disorders • Rare Diseases • Transplantation

Towards Automated Engineering of Donor-Derived T Lymphocytes into CRISPR/Cas9-Mediated CAR T Cells in a Closed-System (ASH 2023) - "AZD7648 reduced the MOI needed for viral transduction by 50% while maintaining 80% or higher levels of transgene knock-in efficiency...We show that metabolic reprogramming can be combined with precision genome editing to generate controllable CART cells. Finally, our data demonstrate the feasibility of automating CRISPR/Cas9-mediated engineering of CAR T cells within closed-system."

CAR T-Cell Therapy • Hematological Malignancies • Leukemia • Oncology • IL2

An in situ immunogenicity-amplifying payload delivery system for immunotherapy of Kirsten rat sarcoma viral oncogene homolog-mutant cancer. (PubMed, J Control Release) - "When combined with the DNA damage repair inhibitor AZD7648 to enhance immunogenic cell death (ICD), the MPD1-based therapy triggered robust pyroptosis and upregulated ICD markers on tumor cells...Rechallenge studies confirmed the establishment of robust immunological memory. This work establishes a new engineering paradigm with a self-amplifying, ICD-inducing therapy for treating historically "undruggable" cancers, creating a strategy to convert resistant tumors into ones that are highly susceptible to immunotherapy with clinically usable drugs."

IO biomarker • Journal • Preclinical • Colorectal Cancer • Oncology • Sarcoma • Solid Tumor • CASP3 • CD40 • CD8 • CD86 • IFNG • IL18 • KRAS • TNFA

Characterising designer nuclease activity and DNA repair mechanisms with MEGA dPCR and high-resolution CAST-Seq (ESGCT 2024) - "To quantify chromosomal aberrations, we performed MEGA dPCR and CAST-Seq on CRISPR-Cas9-edited haematopoietic stem and progenitor cells (HSPCs) cultured with an end-joining repair inhibitor cocktail (ART558 and AZD7648). Seeking to adopt repair-inhibiting compounds may improve integration efficacy, but at the cost of genome destabilisation and increasing the risk of generating genotoxic by-products. We propose that utilising DSB repair-inhibiting compounds necessitates a careful specificity evaluation for potential clinical use but nonetheless has value for enhancing the sensitivity of techniques that detect designer nuclease-mediated mutations and characterising DSB generation and repair dynamics."

Gene Therapies

Simultaneous inhibition of DNA-PKcs and 53BP1 enables the enrichment-free replacement of the CFTR cDNA in airway basal stem cells (NACFC 2025) - "Overall, the combined inhibition of NHEJ using AZD-7648 and UbVa enhanced CFTR cDNA insertion by 8-fold in primary ABCs without significant cytotoxicity. This method successfully restored CFTR protein expression and function in differentiated airway epithelial cells from one donor. Further evaluation of CFTR function is ongoing in cells from additional donors."

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

Investigating the combinatorial effects of ACE-tRNAs and small molecules to suppress CF-causing nonsense mutations (NACFC 2025) - "Figure 1 (abstract 279): Simultaneous AZD-7648 and UbVa treatment enhances gene insertion in primary ABCs using the dual-vector strategy...Additionally, several small molecules with differing mechanisms of actions have been shown to readthrough PTCs, such as G418, PTC124, SRI-41315 and CC-90009... Currently, experiments to determine the optimal ACE-tRNA + small molecule combinations are being performed."

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

L-arginine synergistic with 5-fluorouracil intervenes in DNA damage repair via the DNA-PKcs/ATM/ATR pathway in hepatocellular carcinoma cells. (PubMed, Acta Biochim Biophys Sin (Shanghai)) - "AZD-7648 (a DNA-PKcs inhibitor) and LY294002 (a PI3K inhibitor) enhance p-ATM and p-ATR activation, resulting in elevated apoptosis and increased γ-H2AX expression. These findings are validated in a DEN-induced rat liver cancer model. In summary, 5-FU and L-Arg synergistically increase iNOS/NO-driven ROS accumulation, inducing γ-H2AX-marked DNA damage through dual modulation of repair pathways (inhibiting PI3K/AKT/DNA-PKcs while activating ATM/ATR), ultimately triggering p53-mediated G2/M arrest and apoptosis in hepatocellular carcinoma cells."

IO biomarker • Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • BAX • BCL2 • BRCA1 • CASP3 • CASP9 • CHEK1 • CHEK2 • H2AX

Refined DNA repair manipulation enables a universal knock-in strategy in mouse embryos. (PubMed, Nat Commun) - "Finally, by combining AZD7648 treatment with Polq knockdown, we develop a universal and highly efficient knock-in strategy in mouse embryos. This approach is validated at more than ten genomic loci, achieving up to 90% knock-in efficiency, marking a significant advancement toward predictable and highly efficient CRISPR-mediated gene integration."

Journal • Preclinical • POLQ

Targeting the chromatin remodeler HELLS to Improve Therapeutic Strategies in T-Cell Lymphoma (EACR 2025) - "These findings demonstrate the direct role of HELLS in transcriptional regulation and pave the way for the development of targeted and clinically translatable strategies for HELLS inhibition."

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

DISSECTING THE HELLS GENE SIGNATURE IN ANAPLASTIC LARGE CELL LYMPHOMA: IMPLICATIONS FOR DRUG REPURPOSING AND COMBINATION THERAPY (EHA 2025) - "To validate these results, we treated HELLSKD and control cells with IC20 dose of a representative compound of each class (BKM-120 for PI3K, Ruxolitinib for JAK1/2, AZD7648 for DNA-PK). Collectively, these findings pave the way for the development of effective and clinically translatable strategies for HELLS inhibition. Such pharmacological inhibitors hold promise not only as monotherapy but also in synergistic combination with conventional and targeted therapies"

Combination therapy • Gene Signature • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ALK • HELLS • IFNG • JAK1 • JAK2

OVERCOMING CHEMOTHERAPY RESISTANCE THROUGH TARGETED INHIBITION OF DNA-PK-DEPENDENT DNA REPAIR. (EHA 2025) - "High-throughput drug screening, Synergism scoring, Western blot, Cell cycle with yH2AX analysis, Apoptosis assay with AnnexinV, in vivo experiment with AML Patient-derived Xenograft(PDX) mouse model.High-throughput drug response testing of the DNA-PKi AZD7648 and chemotherapy alone and in combination demonstrated that inhibition of DNA-PK synergistically enhanced chemotherapy response across seven AML cell lines (TP53mut/del, n=5; TP53wt, n=2) and TP53mut/del AML patient samples (n=3)... Combinatorial treatment with chemotherapy and a DNA-PK inhibitor synergistically inhibited growth and survival of AML cells in vitro and significantly prolonged survival of mice with AML compared to untreated or single-treated mice. Our findings highlight the potential of DNA-PKi to improve response and overcome chemotherapy resistance in both TP53wt and TP53mut/del AML patients.Reference:PMID: 35797463PMID: PMC2754209PMID:33299144"

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BCL2 • MCL1

Application of Biological Modifiers to a Multiplexed, Human Cell-Based DNA Damage Assay Provides Mechanistic Information on Genotoxicity and Molecular Targets. (PubMed, Environ Mol Mutagen) - "Cells were exposed in 96-well plates in the presence and absence of each of four modifying agents at one optimized concentration: talazoparib (PARP inhibitor), MK-8776 (CHK1 inhibitor), AZD-7648 (DNA-PK inhibitor), or a cocktail of reactive oxygen species scavengers. Unsupervised hierarchical clustering of the collective potency metrics for various combinations of biomarkers showed that clastogens with similar genotoxic mechanisms grouped together. Overall, this study shows that in combination with biological response modifiers, MultiFlow and In Vitro MicroFlow biomarkers can provide mechanistic insights into chemical-induced genotoxicity."

Journal

A hybrid gene correction strategy for Cystic Fibrosis (ASGCT 2025) - "The correction efficiency could be further enhanced by using AZD7648, an inhibitor of DNA-PK, achieving up to 81% corrected alleles. We are now validating this therapeutic approach in more advanced models such as precision-cut human lung slices. Disease Focus of Abstract:Cystic Fibrosis"

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

Genome editing with AZD7648 induces large-scale genomic alterations (ASGCT 2025) - "We found that genome editing with AZD7648 causes frequent kilobase-scale and megabase-scale deletions, chromosome arm loss and translocations. These large-scale chromosomal alterations evade detection through typical genome editing assays, prompting caution in deploying AZD7648 and reinforcing the need to investigate multiple types of potential editing outcomes."

Site-Specific Gene Integration Strategies for IL7Rα-SCID Hematopoietic Stem Cell Gene Therapy (ASGCT 2025) - "We tackled this issue by adding AZD7648, a potent DNA-PK inhibitor, to influence DNA repair further towards the HDR pathway while adding lower amounts of the donor template...Crucially, we are also looking into sequence fidelity of the integrated transgenes due to reports of IL7Rα gain-of-function mutations in Leukemia patients. Disease Focus of Abstract:Immunodeficiency"

Gene therapy • Gene Therapies • Hematological Malignancies • Immunology • Leukemia • Oncology • Primary Immunodeficiency • CD34 • IL7 • IL7R

The DNA-PK inhibitor AZD7648 alone or combined with pegylated liposomal doxorubicin in patients with advanced cancer: results of a first-in-human Phase I/IIa study. (PubMed, Br J Cancer) - P1/2 | "Toxicity of AZD7648 + PLD was greater than expected and antitumour activity was limited, leading to early study termination."

Journal • P1/2 data • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Oncology

The DNA-PK inhibitor AZD7648 alone or combined with pegylated liposomal doxorubicin in patients with advanced cancer: results of a first-in-human Phase I/IIa study (Nature, Br J Cancer) - P1/2a | N=30 | NCT03907969 | Sponsor: AstraZeneca | "AZD7648 monotherapy was administered at 5–160 mg BID. The most frequent class of adverse events was gastrointestinal disorders (9/14 patients, 64.3%); one patient (160 mg BID) experienced dose-limiting toxicities (DLTs). No responses to AZD7648 monotherapy were observed. The maximum dose of combination therapy was AZD7648 40 mg QD days 1–7 + PLD every 28 days. 13/16 patients (81.3%) experienced gastrointestinal disorders and 11/16 (68.8%) patients had anaemia. Three patients experienced DLTs (two at AZD7648 20 mg QD 7 days + PLD; one at AZD7648 30 mg QD 7 days + PLD). Limited efficacy was observed, with one RECIST partial response."

P1/2 data • Solid Tumor

The DNA-PK inhibitor AZD7648 alone or combined with pegylated liposomal doxorubicin in patients with advanced cancer: results of a first-in-human Phase I/IIa study (Nature, Br J Cancer) - P1/2a | N=30 | NCT03907969 | Sponsor: AstraZeneca | "AZD7648 monotherapy was administered at 5–160 mg BID. The most frequent class of adverse events was gastrointestinal disorders (9/14 patients, 64.3%); one patient (160 mg BID) experienced dose-limiting toxicities (DLTs). No responses to AZD7648 monotherapy were observed. The maximum dose of combination therapy was AZD7648 40 mg QD days 1–7 + PLD every 28 days. 13/16 patients (81.3%) experienced gastrointestinal disorders and 11/16 (68.8%) patients had anaemia. Three patients experienced DLTs (two at AZD7648 20 mg QD 7 days + PLD; one at AZD7648 30 mg QD 7 days + PLD). Limited efficacy was observed, with one RECIST partial response."

P1/2 data • Solid Tumor