Exploring AZD7648: A Targeted Therapy for DNA-PK Inhibition and Its Impact on Tumor Growth

The DNA-dependent kinase (DNA-PK) is integral to the non-homologous end joining (NHEJ) process, playing a crucial role in the detection and repair of DNA double strand breaks (DSBs). It is a significant element of the DNA Damage Response (DDR), and its inhibition can sensitize cells to DNA damage-inducing agents such as chemotherapy, radiation, or PARP inhibitors. DNA-PK inhibitors are also potentially effective as single agents in tumors with high intrinsic DNA damage due to deficiencies in other DNA repair mechanisms.

We have developed AZD7648, a highly potent and selective DNA-PK inhibitor, which has demonstrated broad inhibitory activity against a range of cancer cell lines. AZD7648 shows a significantly greater growth inhibitory effect in cell lines with ATM knockout (KO), indicating a synthetic lethal interaction with DNA-PK. This correlates with an increase in DNA damage, as evidenced by micronuclei formation and chromosomal break analysis.

In vivo studies have shown that AZD7648 treatment inhibits tumor growth in various patient-derived xenograft (PDX) and xenograft models of breast, lung, ovarian, and head and neck cancers, including those with and without ATM loss. The treatment led to a dose-dependent decrease in the phosphorylation of DNA-PK, RPA32, and nuclear γH2AX, particularly in FaDu ATM KO xenografts. These findings confirm that AZD7648 has strong pharmacodynamic effects and exhibits monotherapy anti-tumor activity in a variety of pre-clinical models, particularly in those with engineered or inherent ATM loss.

This abstract highlights the development and evaluation of AZD7648, a DNA-PK inhibitor, and its potential as a therapeutic agent in cancer treatment, particularly in the context of ATM deficiency and DNA repair dysfunction.