Highlights
- Exhibits minimal off-target effects with superior selectivity for DNA-PK versus closely related kinases, PI3K, ATM, ATR & mTOR
- Synergises with standard of care treatments that increase DSB incidence; sensitising cancers to ionising radiation (IR), topoisomerase II (doxorubicin) and PARP inhibitors
- Single agent and combinations induced tumour regression in non-small cell lung, breast (TNBC), ovarian, and head and neck cancer xenografts including some ATM-deficient, BRAC1 and TP53 mutants PDX
The opportunity
DNA-PK plays a central role in DNA Damage Responses, coordinating double-strand break (DSB) repair via the non-homologous end joining (NHEJ) pathway. In several solid tumours and haematological malignancies, DNA-PK is frequently overexpressed or dysregulated, promoting aggressive metastatic progression and resistance to DSB-inducing agents (RTx and TopII inhibitors). This dependency renders DNA-PK an attractive therapeutic target; however, first-generation DNA-PK inhibitors were hampered by poor selectivity, metabolic instability and suboptimal pharmacokinetics.
AZD7648 is differentiated from its competitors as it demonstrates high selectivity for DNA-PK versus related kinases (PI3K, ATM, ATR, mTOR) and effectively sensitises tumours to DSB-inducing agents. By blocking DNA-PK autophosphorylation, AZD7648 suppresses NHEJ-mediated DSB repair, thereby exacerbating genomic instability and promoting apoptosis (IC₅₀ = 91.3 nM).
AZD7648 monotherapy and combinations induced significant tumour regression in non-small cell lung, breast (TNBC), ovarian, and head and neck cancer xenografts including some ATM-deficient, BRAC1 and TP53 mutants PDX. In vivo, AZD7648 is an impressive chemo- and radiosensitiser and also demonstrates synergy with PARP inhibition.
In 2019, an open-label Phase I/IIa trial launched to evaluate AZD7648 in advanced malignancies as a single agent and in combination with pegylated liposomal doxorubicin (PLD).