AZD7648 / AstraZeneca - LARVOL DELTA

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

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 • Bone Marrow Transplantation • Gene Therapies • Hematological Malignancies • Immunology • Leukemia • Oncology • Primary Immunodeficiency • CD34 • IL7 • IL7R

N-(5-(2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)pyridin-2-yl)acylamides as novel multi-PI3K/DNA-PK/P-gp inhibitors for efficient chemosensitization and MDR alleviation. (PubMed, Eur J Med Chem) - "Compared to a commercial DNA-PK/PI3K inhibitor AZD7648, synthesized compounds generally exhibited markedly lower baseline cytotoxicity in all tested cell lines (MC38, B16F10, 4T1, CT26 and HEK-239)...While in cell-free conditions, 6 acted as a very efficient pan-PI3K and DNA-PK inhibitor, in physiological conditions, 2 performed better and acted as a potent chemosensitizer able to increase the amount of DNA double strand breaks induced by doxorubicin...We also demonstrate that 2 can be simply loaded into lipid nanoparticles that retain its chemosensitizing properties. Taken together, the presented study provides a solid basis for a subsequent rational structure optimization towards new generation of multitarget inhibitors able to control crucial signaling pathways involved in tumorigenesis and drug resistance."

Journal • Oncology • ABCC1

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

AZD7648 (DNA-PKcs inhibitor): a two-edged sword for editing genomes. (PubMed, Funct Integr Genomics) - "published in Nature Biotechnology showed interesting features of AZD7648 (a DNA-PKcs inhibitor) that increase the probability of HDR event while DNA repairing (Cullot et al. 2024)."

Journal

DNA-PK inhibition enhances gene editing efficiency in HSPCs for CRISPR-based treatment of X-linked hyper IgM syndrome. (PubMed, Mol Ther Methods Clin Dev) - "Our combined findings demonstrate HDR editing at the CD40LG locus at potentially clinically beneficial levels. More broadly, these data support using DNA-PKcs inhibition with AZD7648 as a simple and efficacious addition to HSPC editing platforms."

Journal • Immunology • Primary Immunodeficiency • Transplantation • CD34 • CD40LG

Defining preclinical efficacy with the DNAPK inhibitor AZD7648 in combination with olaparib: a minimal systems pharmacokinetic-pharmacodynamic model. (PubMed, J Pharmacokinet Pharmacodyn) - "Furthermore, the model can be utilized to assess what exposures would be necessary in the clinic by linking it to observed or predicted human PK exposures. The model suggests 64.9 uM olaparib is sufficient to achieve tumor stasis in the absence of AZD7648, while the combination of AZD7648 and olaparib only requires plasma concentrations of 20.2 uM AZD7648 and 19.9 uM olaparib at steady-state to achieve the same effect."

Journal • PK/PD data • Preclinical • Oncology

Enhanced fetal hemoglobin production via dual-beneficial mutation editing of the HBG promoter in hematopoietic stem and progenitor cells for β-hemoglobinopathies. (PubMed, Stem Cell Res Ther) - "Cas9 RNP-ssODN-based nucleotide conversion at the HBG promoter offers a promising gene therapy approach to ameliorate the phenotypes of β-thalassemia and SCD. The developed approach can simplify and broaden applications that require the cointroduction of multiple nucleotide modifications in HSPCs."

Journal • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Enhanced radiosensitivity of head and neck cancer cells to proton therapy via hyperthermia-induced homologous recombination deficiency. (PubMed, Clin Transl Radiat Oncol) - "In this study, we examined the response of FaDu cells, a head and neck squamous cell carcinoma model, to spread-out Bragg peak (SOBP) proton and photon radiation combined with mild hyperthermia (42 °C for one hour) to induce homologous recombination deficiency or NHEJ inhibition by AZD7648...These findings support the hypothesis that cells rely more on homologous recombination to repair proton-induced DNA damage compared to photon-induced DNA damage. As clinically applied hyperthermia enhances the therapeutic effect of photon irradiation by, among other factors, inducing homologous recombination deficiency, our results suggests that hyperthermia could be more effective in combination with proton irradiation than photon irradiation."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • HRD • RAD51

BCCA7693 - A novel, orally bioavailable DNA-PK inhibitor demonstrates efficacy with targeted MAPK and PARP therapeutics by slowing the development of acquired resistance (EORTC-NCI-AACR 2024) - "Biochemical and cellular screening assays were used to identify compounds having high potency, selectivity and desirable ADME characteristics, comparable to those recently evaluated by clinical trials in combinations with DNA-damaging anti-cancer treatments including radiotherapy (AZD7648 and M3814)...In recent in vitro and in vivo studies, BCCA7693 has also demonstrated efficacy with targeted therapeutics, decreasing tumour cell survival during replicative stress and thereby blocking the development of acquired resistance induced by a variety of MAPK, RTK and PARP inhibitors (Trametinib, Adagrasib, Dabrafenib, Afatinib and Olaparib). Crucially, in contrast to radio- and chemotherapy, murine studies with BCCA7693 did not result in increased toxicity for combination treatments with molecular targeted therapeutics, suggesting the potential for an additional clinical application of this DSB repair inhibitor. In Conclusion, BCCA7693, shows potential for combination with a..."

Clinical • Late-breaking abstract • Preclinical • Oncology • PARP1

Genome editing with the HDR-enhancing DNA-PKcs inhibitor AZD7648 causes large-scale genomic alterations. (PubMed, Nat Biotechnol) - "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."

Journal

DNA-PKcs inhibition improves sequential gene insertion of the full-length CFTR cDNA in airway stem cells. (PubMed, Mol Ther Nucleic Acids) - "To improve CFTR cDNA insertion in human airway basal stem cells (ABCs), we evaluated the use of the small molecules AZD7648 and ART558, which inhibit non-homologous end-joining (NHEJ) and micro-homology mediated end-joining (MMEJ). Adding AZD7648 did not increase off-target editing. Further studies are necessary to validate if AZD7648 treatment enriches cells with oncogenic mutations."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases • CFTR

DNA-PKcs Inhibition Improves Sequential Gene Insertion of the Full-Length CFTR cDNA in Airway Stem Cells. (PubMed, bioRxiv) - "To improve CFTR cDNA insertion in human airway basal stem cells (ABCs), we evaluated the use of the small molecules AZD7648 and ART558 which inhibit non-homologous end joining (NHEJ) and micro-homology mediated end joining (MMEJ). Adding AZD7648 did not increase off-target editing. Further studies are necessary to validate if AZD7648 treatment enriches cells with oncogenic mutations."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases • CFTR

PRKDC Induces Chemoresistance in Osteosarcoma by Recruiting GDE2 to Stabilize GNAS and Activate AKT. (PubMed, Cancer Res) - "Using a kinome-wide CRISPR screen, we identified PRKDC as a critical determinant of doxorubicin (DOX) sensitivity in osteosarcoma. The PRKDC inhibitor AZD7648 and DOX synergized and strongly suppressed the growth of osteosarcoma in mouse xenograft models and human organoids. In conclusion, the PRKDC-GDE2-GNAS-AKT regulatory axis suppresses DOX sensitivity and comprises targetable candidates for improving the efficacy of chemotherapy in osteosarcoma."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • GNAS • PRKDC

DNA-PKcs Inhibition Sensitizes Human Chondrosarcoma Cells to Carbon Ion Irradiation via Cell Cycle Arrest and Telomere Capping Disruption. (PubMed, Int J Mol Sci) - "A time-dependent shortening of telomere length was observed in both cell lines after combined treatment with AZD7648 and 8 Gy X-ray/C-ion IR. Our data suggest that the inhibition of DNA-PKcs may increase sensitivity to X-rays and C-ion IR by impairing its functional role in DNA repair mechanisms and telomere end protection."

Journal • Oncology • Sarcoma • Solid Tumor • CDK1 • CHEK2

Effective Radiosensitization of HNSCC Cell Lines by DNA-PKcs Inhibitor AZD7648 and PARP Inhibitors Talazoparib and Niraparib. (PubMed, Int J Mol Sci) - "Healthy fibroblasts tolerated AZD7648 alone extremely well, but irradiation-induced effects might occur. Our results justify in vivo studies."

Journal • Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ANXA5

Stimulating macropinocytosis of peptide-drug conjugates through DNA-dependent protein kinase inhibition for treating KRAS-mutant cancer. (PubMed, J Control Release) - "AZD7648 possesses broad applications in augmenting nano-sized drug delivery and preventing DNA repair resistance. The promising efficacy and evident synergy underscore the potential of combining MPD1 with AZD7648 as a strategy for treating KRAS-mutant cancers."

Journal • Oncology • CASP3 • KRAS

Inhibition of key DNA double strand break repair protein kinases enhances radiosensitivity of head and neck cancer cells to X-ray and proton irradiation. (PubMed, Cell Death Discov) - "Using inhibitors targeting ATM (AZD1390), ATR (AZD6738) and DNA-Pkcs (AZD7648), we observed that this led to significantly decreased clonogenic survival of HNSCC cell lines following both X-ray and proton irradiation. We confirmed that the inhibitors in combination with X-rays and protons led to DSB persistence, and increased micronuclei formation. Cumulatively, our data suggest that targeting DSB repair, particularly via ATM and DNA-Pkcs inhibition, can exacerbate the impact of ionising radiation in sensitising HNSCC cell models."

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

Near-perfect precise on-target editing of human hematopoietic stem and progenitor cells. (PubMed, Elife) - "The main protocol modifications needed to achieve such high efficiencies were the addition of the DNA-PK inhibitor AZD7648, and the inclusion of spacer-breaking silent mutations in the donor in addition to mutations disrupting the PAM sequence...With these optimizations, editing at near-perfect efficiency can now be accomplished directly in human HSPCs. This will open new avenues in both therapeutic strategies and disease modelling."

Journal • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

Radiation and chemo-sensitizing effects of DNA-PK inhibitors are proportional in tumors and normal tissues. (PubMed, Mol Cancer Ther) - "Similar effects were seen in the intestinal jejunum, tongue and FaDu tumor xenografts of mice assessed for proliferation rates at 3.5 days after treatment with etoposide or 5Gy whole body irradiation ± DNA-PK inhibitors AZD7648 or peposertib (M3814). DNA-PK inhibitor-mediated sensitization to radiation and DNA-damaging chemotherapy is not limited to tumor tissues, but also extends to normal tissues sustaining DNA damage. These data are useful for interpretation of the sensitizing effects of DNA damage repair inhibitors, where a therapeutic index showing greater cell-killing effects on cancer cells is crucial for optimal clinical translation."

Journal • Oncology • ATM

DNA-PK inhibitor AZD7648 is a more portent radiosensitizer than PARP inhibitor Olaparib in BRCA1/2 deficient tumors. (PubMed, DNA Repair (Amst)) - "Conversely, PARP inhibitors exhibit selective activity for proliferating cells, providing a mechanism for targeting activity to cancers, but due to poor activity in non-proliferating cells they have an overall reduced impact on tumor growth control. This study highlights the importance of creating a therapeutic ratio with DNA damage repair inhibition radiation sensitizing strategies."

Journal • Oncology • BRCA1 • BRCA2

Simultaneous inhibition of DNA‐PK and Polϴ improves integration efficiency and precision of genome editing (ESGCT 2023) - "Combined treatment with AZD7648 and Polϴ inhibitors (which we named 2iHDR) substantially increased the precision of templated insertions, with efficiencies of up to 80% and nearly no formation of undesired Insertion-Deletions (InDels). Notably, 2iHDR also reduced Cas9-associated off-target activity, greatly improving the performance and fidelity of CRISPR-Cas9 gene editing."

Genetic Disorders

High frequency HDR gene editing of γ‐globin promoters produces therapeutic levels of fetal hemoglobin in‐vivo (ESGCT 2023) - "Furthermore, in our screen testing across small molecule enhancers, DNA-PK inhibitor AZD-7648 outperformed others in improving HDR gene editing in HSPCs...The engraftment of -175T>C, -158C>T dual genetic variant HSPCs also contributed up to 45.7% F+ve cells in-vivo. Our study suggests that careful screening of ssODN design, dosage, culture and editing conditions, enables the generation of high frequency, durable HDR editing in HSPCs."

Preclinical • Hematological Disorders • Transplantation

Repurposed DNA Repair Inhibitors to Enhance Targeted Integration Drastically Increases Chromosomal Instability (ASGCT 2024) - "To explore this, we cultured CRISPR-Cas9 edited haematopoietic stem and progenitor cells (HSPCs) with an end-joining repair inhibitor cocktail (ART558 and AZD7648) and performed CAST-Seq and digital PCR (dPCR) to quantify aberrations. 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 repairinhibiting compounds may be better suited as sensitivityenhancing agents to improve the resolution of existing offtarget and aberration-detecting techniques."

Late-breaking abstract • Gene Therapies

Enhancing standard of care chemotherapy efficacy using DNA-dependent protein kinase (DNA-PK) inhibition in preclinical models of Ewing sarcoma. (PubMed, Mol Cancer Ther) - "In vivo, the combination of AZD-7648 and etoposide had limited tolerability but resulted in enhanced DNA damage, apoptosis, and EWS tumor shrinkage. The combination of DNA-PKi with standard of care TOP2 poisons in EWS models is synergistic, enhances DNA damage and cell death, and may form the basis of a promising future therapeutic strategy for EWS."

Journal • Preclinical • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor