Q4
Phase I Best-in-Class DNA-Dependent Protein Kinase (DNA-PK) Inhibitor: AZD7648
Dr Maurice Raymond, AstraZeneca ; Dr Frederick Woolf Goldberg, AstraZeneca; Dr Verschoyle Finlay, AstraZeneca ; Dr Attilla Kuan Tsuei Ting, AstraZeneca
Cancer Research Horizons
Challenge
DNA-PK plays a central role in DNA Damage Responses, coordinating double-strand break (DSB) repair via the non-homologous end joining (NHEJ) pathway. However, 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 inhibitors were hampered by limited selectivity, metabolic instability and suboptimal pharmacokinetics.
Technology
Developed by AstraZeneca & Cancer Research Horizons, AZD7648 is a highly potent and selective small molecule DNA-PK inhibitor with favourable PK/PD properties and on-target coverage at achievable clinical exposure. By blocking DNA-PK autophosphorylation, AZD7648 suppresses NHEJ-mediated DSB repair, thereby exacerbating genomic instability and promoting apoptosis (IC₅₀ = 91.3 nM in A549 NSCLC cells).
AZD7648 also exhibits minimal off-target effects with superior selectivity for DNA-PK versus closely related kinases; PI3K, ATM, ATR, mTOR. DNA-PK inhibition sensitises cancers to DNA-damaging modalities: in vivo, AZD7648 combined with ionising radiation achieved marked tumour growth inhibition (e.g., 85% TGI in NCI-H1299 NSCLC at 100 mg/kg + 5×2 Gy), RTx+AZD7648 leads to durable immune-mediated tumour control when type I IFN is blocked.
AZD7648 also potentiated liposomal doxorubicin, increasing tumour regression across solid tumour models, including TNBC (BT474 xenografts 63% TGI with doxorubicin alone, 77% in combination). Synergistic activity was also observed with PARP inhibition (complete regression in FaDU ATM-KO xenografts with olaparib). Fundamentally, AZD7648's selectivity, favourable PK/PD profiles, and impressive chemo-/radio-sensitisation supported progress to a Phase I/IIa trial.
Commercial Opportunity
AZD7648 is a Phase I asset with best-in-class potential; CRH are seeking partners to advance AZD7648 clinical development by optimising its use in defined cancers, exploring strategic combinations and targeted approaches. We especially welcome licensing and/or collaboration opportunities with companies focused strongly on RTx to SBRT, TopII inhibitors, ADCs, radioimmunoconjugates or CRISPR-Cas9 genome editing technologies.
Development Status
NCT03907969: Phase I/IIa study initially planned and aimed to investigate AZD7648 as a monotherapy, or in combination with pegylated liposomal doxorubicin (PLD) in participants with advanced solid tumours. Phase I was completed, and clinical data were published. Progression to Phase IIa terminated. CRH are keen to collaborate with partners on alternative clinical hypotheses.
Patent Situation
WO2018114999A1 (lead series) and WO2019238929 (second series), composition of matter patents were filed in 2017 and 2019 respectively, by AstraZeneca and CRH. Patents cover amino-triazolopyridine or purinone compounds and their use in treating cancers. CRH is leading the commercialisation of AZD7648.
Further Reading
- https://www.nature.com/articles/s41467-019-12836-9
- https://www.nature.com/articles/s41416-025-03053-x
- https://pmc.ncbi.nlm.nih.gov/articles/PMC9401489/
- https://link.springer.com/article/10.1007/s10142-025-01560-x
