AZD7648

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.

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.

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.

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.

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.

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.

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.

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.

Healthy fibroblasts tolerated AZD7648 alone extremely well, but irradiation-induced effects might occur. Our results justify in vivo studies.

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.

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.

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.