Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors.
Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors.
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ST-162 和 ST-168 作为新型双功能 MEK/PI3K 抑制剂的眼部毒性特征。
DOI：
10.1089/jop.2017.0126
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Besirli,CagriG
中科院分区：
文献类型：
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作者：
Smith,Andrew;Pawar,Mercy;VanDort,MarcianE;Galbán,Stefanie;Welton,AmandaR;Thurber,GregM;Ross,BrianD;Besirli,CagriG
用途：ST-162 和 ST-168 是 MEK 和 PI3K 信号通路的小分子双功能抑制剂，正在开发为新型抗肿瘤药物。之前的小分子和生物 MEK 抑制剂在临床研究中表现出剂量限制的眼部毒性事件。我们评估了 ST-162 和 ST-168 的体外和体内眼毒性特征。方法：用浓度不断增加的双功能抑制剂处理感光细胞系 661W 和成人视网膜色素上皮细胞系 ARPE-19。通过蛋白质印迹、细胞活力和半胱天冬酶活性测定来评估 MEK 和 PI3K 抑制和剂量依赖性体外毒性，并与单一疗法进行比较。通过在荷兰带兔中玻璃体内注射 ST-162 和 ST-168 评估体内毒性特征，然后对去核眼进行眼部检查和组织学分析。结果：用 ST-162 或 ST-168 处理的视网膜细胞系表现出剂量依赖性抑制 MEK 和 PI3K 信号传导。与单一疗法及其组合的抑制相比，双功能抑制剂表现出减少的细胞死亡和caspase活性。在体内，与MEK抑制剂PD0325901相比，两种双功能抑制剂表现出更有利的毒性特征。结论：新型MEK和PI3K双功能抑制剂ST-162和ST-168表现出良好的体外和体内眼毒性特征，支持其进一步开发为针对多种侵袭性肿瘤的潜在治疗剂。
Purpose:ST-162 and ST-168 are small-molecule bifunctional inhibitors of MEK and PI3K signaling pathways that are being developed as novel antitumor agents. Previous small-molecule and biologic MEK inhibitors demonstrated ocular toxicity events that were dose limiting in clinical studies. We evaluatedin vitroandin vivoocular toxicity profiles of ST-162 and ST-168.Methods:Photoreceptor cell line 661W and adult retinal pigment epithelium cell line ARPE-19 were treated with increasing concentrations of bifunctional inhibitors. Western blots, cell viability, and caspase activity assays were performed to evaluate MEK and PI3K inhibition and dose-dependentin vitrotoxicity, and compared with monotherapy.In vivotoxicity profile was assessed by intravitreal injection of ST-162 and ST-168 in Dutch-Belted rabbits, followed by ocular examination and histological analysis of enucleated eyes.Results:Retinal cell lines treated with ST-162 or ST-168 exhibited dose-dependent inhibition of MEK and PI3K signaling. Compared with inhibition by monotherapies and their combinations, bifunctional inhibitors demonstrated reduced cell death and caspase activity.In vivo, both bifunctional inhibitors exhibited a more favorable toxicity profile when compared with MEK inhibitor PD0325901.Conclusions:Novel MEK and PI3K bifunctional inhibitors ST-162 and ST-168 demonstrate favorablein vitroandin vivoocular toxicity profiles, supporting their further development as potential therapeutic agents targeting multiple aggressive tumors.