The Discovery of 7‑Methyl-2-[(7-methyl[1,2,4]triazolo[1,5‑a]pyridin-6-yl)amino]-9-(tetrahydro‑2H‑pyran-4-yl)-7,9-dihydro‑8H‑purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor

DNA-PK
is a key component within the DNA damage response, as it
is responsible for recognizing and repairing double-strand DNA breaks
(DSBs) via non-homologous end joining. Historically it has been challenging
to identify inhibitors of the DNA-PK catalytic subunit (DNA-PKcs)
with good selectivity versus the structurally related PI3 (lipid)
and PI3K-related protein kinases. We screened our corporate collection
for DNA-PKcs inhibitors with good PI3 kinase selectivity, identifying
compound 1. Optimization focused on further improving
selectivity while improving physical and pharmacokinetic properties,
notably co-optimization of permeability and metabolic stability, to
identify compound 16 (AZD7648). Compound 16 had no significant off-target activity in the protein kinome and
only weak activity versus PI3Kα/γ lipid kinases. Monotherapy
activity in murine xenograft models was observed, and regressions
were observed when combined with inducers of DSBs (doxorubicin or
irradiation) or PARP inhibition (olaparib). These data support progression
into clinical studies (NCT03907969).

DNA-PK（DNA损伤反应的关键组分）负责通过非同源末端连接识别和修复双链DNA断裂（DSBs）。历史上，由于该蛋白激酶催化亚基（DNA-PKcs）与结构相关的PI3（脂质）和PI3K相关蛋白激酶的特异性较低，因此寻找具有良好选择性的DNA-PKcs抑制剂一直颇具挑战。本研究对公司收藏的化合物库进行了筛选，以识别具有良好PI3激酶选择性的DNA-PKcs抑制剂，并最终鉴定出化合物1。优化工作着重于进一步提高选择性，同时改善物理和药代动力学特性，特别是渗透性和代谢稳定性的协同优化，从而筛选出化合物16（AZD7648）。化合物16在蛋白质激酶组中显示出无显著脱靶活性，且与PI3Kα/γ脂质激酶的活性较弱。在小鼠异种移植模型中观察到单药治疗活性，并且当与DSBs诱导剂（多柔比星或辐射）或PARP抑制（奥拉帕利）联合使用时，观察到肿瘤退缩。这些数据支持该化合物进入临床研究阶段（NCT03907969）。