Goldberg Frederick W, Ting Attilla K T, Beattie David, Lamont Gillian M, Fallan Charlene, Finlay M Raymond V, Williamson Beth, Schimpl Marianne, Harmer Alexander R, Adeyemi Oladipupo B, Nordell Pär, Cronin Anna S, Vazquez-Chantada Mercedes, Barratt Derek, Ramos-Montoya Antonio, Cadogan Elaine B, Davies Barry R
Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
ACS Med Chem Lett. 2022 Jul 7;13(8):1295-1301. doi: 10.1021/acsmedchemlett.2c00172. eCollection 2022 Aug 11.
The DNA-PK complex is activated by double-strand DNA breaks and regulates the non-homologous end-joining repair pathway; thus, targeting DNA-PK by inhibiting the DNA-PK catalytic subunit (DNA-PKcs) is potentially a useful therapeutic approach for oncology. A previously reported series of neutral DNA-PKcs inhibitors were modified to incorporate a basic group, with the rationale that increasing the volume of distribution while maintaining good metabolic stability should increase the half-life. However, adding a basic group introduced hERG activity, and basic compounds with modest hERG activity (IC = 10-15 μM) prolonged QTc (time from the start of the Q wave to the end of the T wave, corrected by heart rate) in an anaesthetized guinea pig cardiovascular model. Further optimization was necessary, including modulation of p , to identify compound , which combines low hERG activity (IC = 75 μM) with excellent kinome selectivity and favorable pharmacokinetic properties.
DNA-PK复合物可被双链DNA断裂激活，并调节非同源末端连接修复途径；因此，通过抑制DNA-PK催化亚基（DNA-PKcs）来靶向DNA-PK可能是一种有用的肿瘤治疗方法。对先前报道的一系列中性DNA-PKcs抑制剂进行修饰，使其含有一个碱性基团，其理论依据是在保持良好代谢稳定性的同时增加分布体积应能延长半衰期。然而，添加碱性基团会引入hERG活性，并且在麻醉豚鼠心血管模型中，具有适度hERG活性（IC = 10 - 15 μM）的碱性化合物会延长QTc（从Q波开始到T波结束的时间，经心率校正）。需要进一步优化，包括对p的调节，以鉴定出化合物，该化合物结合了低hERG活性（IC = 75 μM）、出色的激酶组选择性和良好的药代动力学性质。
