Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents

We previously
reported a novel inhibitor of the ataxia-telangiectasia mutated (ATM)
kinase, which is a target for novel radiosensitizing drugs. While
our initial lead, compound 4, was relatively potent and
nontoxic, it exhibited poor stability to oxidative metabolism and
relatively poor selectivity against other kinases. The current study
focused on balancing potency and selectivity with metabolic stability
through structural modification to the metabolized site on the quinazoline
core. We performed extensive structure–activity and structure–property
relationship studies on this quinazoline ATM kinase inhibitor in order
to identify structural variants with enhanced selectivity and metabolic
stability. We show that, while the C-7-methoxy group is essential
for potency, replacing the C-6-methoxy group considerably improves
metabolic stability without affecting potency. Promising analogues 20, 27g, and 27n were selected based
on in vitro pharmacology and evaluated in murine pharmacokinetic and
tolerability studies. Compound 27g possessed significantly
improve pharmacokinetics relative to that of 4. Compound 27g was also significantly more selective against other kinases
than 4. Therefore, 27g is a good candidate
for further development as a potential radiosensitizer.

此前我们曾报道一款新型共济失调毛细血管扩张症突变（ataxia-telangiectasia mutated, ATM）激酶抑制剂，该激酶是新型放射增敏药物的作用靶点。我们的初代先导化合物4虽具备较强活性与低毒性，但存在氧化代谢稳定性差、对其他激酶选择性相对较差的缺陷。本研究旨在通过对喹唑啉（quinazoline）母核上的代谢位点进行结构修饰，平衡化合物的活性、选择性与代谢稳定性。我们针对该喹唑啉类ATM激酶抑制剂开展了大量构效关系与构质关系研究，以筛选出兼具更高选择性与代谢稳定性的结构变体。研究表明，尽管C-7位甲氧基对维持化合物活性至关重要，但替换C-6位甲氧基可在不影响活性的前提下显著改善代谢稳定性。基于体外药理学评价结果，我们筛选出极具潜力的类似物20、27g与27n，并开展了小鼠药代动力学与耐受性研究。相较于化合物4，27g的药代动力学特性得到显著改善，且对其他激酶的选择性也显著优于4。因此，27g可作为潜在放射增敏剂进行后续开发的优秀候选化合物。