Abstract：
In this work, a novel series of heterotricyclic DNA-PK inhibitors were rationally designed, synthesized, and assessed for their biological activity. In the DNA-PK biochemical assay, most compounds displayed potent enzymatic activity, with IC50 values between 0.11 and 71.5 nM. Among them, SK10 exhibited the most potent DNA-PK-inhibitory activity (IC50 = 0.11 nM). Studies of the mechanism of action indicated that SK10 could lower γH2A.X expression levels and demonstrate optimal synergistic antiproliferative activity against Jurkat cells (IC50 = 25 nM) when combined with doxorubicin. Importantly, in CT26 and B16-F10 tumor-bearing mouse models, the combination therapies of SK10 with chemotherapeutic drug doxorubicin, a PD-L1 antibody, and SWS1 (a potent PD-L1 small-molecule inhibitor) demonstrated superior synergistic anticancer and potential immunomodulatory effects. Furthermore, SK10 possessed favorable in vivo pharmacokinetic properties [e.g., oral bioavailability (F) = 31.8%]. Taken together, SK10 represents a novel heterotricyclic DNA-PK inhibitor with antitumor immune effects and favorable pharmacokinetics.
摘要：
在这项工作中,合理设计了一系列新的杂三环DNA-PK抑制剂，合成，并评估其生物活性。在DNA-PK生化检测中,大多数化合物显示出有效的酶活性，IC50值在0.11和71.5nM之间。其中,SK10表现出最有效的DNA-PK抑制活性(IC50=0.11nM)。作用机制的研究表明，SK10可以降低γH2A。当与多柔比星组合时,X表达水平和显示针对Jurkat细胞的最佳协同抗增殖活性(IC50=25nM)。重要的是,在CT26和B16-F10荷瘤小鼠模型中，SK10与化疗药物阿霉素的联合治疗，PD-L1抗体，和SWS1（一种有效的PD-L1小分子抑制剂）表现出优异的协同抗癌作用和潜在的免疫调节作用。此外，SK10具有良好的体内药代动力学特性[例如，口服生物利用度（F）=31.8%]。一起来看,SK10代表具有抗肿瘤免疫作用和有利的药代动力学的新型杂三环DNA-PK抑制剂。
