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作为DNA损伤响应的关键组分，主要负责通过非同源末端连接机制识别并修复双链DNA断裂（DSBs）。历史上，鉴于其与结构相关的PI3（脂质）及PI3K相关蛋白激酶的相似性，寻找对DNA-PK催化亚基（DNA-PKcs）具有良好选择性的抑制剂一直颇具挑战。本研究团队在内部化合物库中筛选出对PI3激酶具有良好选择性的DNA-PKcs抑制剂，并鉴定出化合物1。优化工作旨在进一步提升选择性与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，最终筛选出化合物16（AZD7648）。化合物16在蛋白激酶组中表现出无显著脱靶活性，对PI3Kα/γ脂质激酶仅展现出微弱活性。在鼠异种移植模型中观察到单药治疗活性，与DSBs诱导剂（多柔比星或辐射）或PARP抑制剂（奥拉帕利）联合应用时，观察到肿瘤退缩。这些数据支持该化合物进入临床研究（NCT03907969）。