E7386 不是特异性的 CBP/β-连环蛋白拮抗剂。
E7386 is not a Specific CBP/β-Catenin Antagonist.
机构信息
Department of Cancer Biology and Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
The Integrative Genomics Core, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA.
出版信息
Curr Mol Pharmacol. 2024;17(1):e290523217409. doi: 10.2174/1874467217666230529114100.
BACKGROUND AND OBJECTIVE
The first clinically evaluated CBP/β-catenin antagonist, PRI-724, displayed an excellent safety profile administered intravenously via continuous infusion. Eisai recently disclosed a third-generation, orally available, reportedly CBP/β-catenin antagonist, E7386. However, several structural features and the reported cytotoxicity of E7386 were unexpected for a specific CBP/β-catenin antagonist. Therefore, we undertook a comparison of E7386 versus the highly specific bona fide CBP/β-catenin antagonists, ICG-001 and C82, the active agents derived from the prodrug PRI-724.
INTRODUCTION
CBP/β-catenin antagonists rebalance the equilibrium between CBP/β-catenin and p300/β-catenin dependent transcription and may be able to treat or prevent many diseases of aging via maintenance of somatic stem cell pool and regulating mitochondrial function and metabolism involved in differentiation and immune cell function. The safety, efficacy, and therapeutic potential of the specific CBP/β-catenin antagonists, ICG-001, and the second-generation compound, C82, the active agent derived from the pro-drug PRI-724, have been studied extensively in a variety of preclinical disease models and in the clinic for oncology and hepatic fibrosis. However, the lack of oral bioavailability has hampered the further development of PRI-724. Thus, Eisai recently proposed a third-generation, orally available, reportedly CBP/β-catenin antagonist E7386. Here, we have performed a comparative analysis of E7386 with the highly specific bona fide CBP/β-catenin antagonists, ICG-001 and C82.
METHODS
We utilized a series of previously validated biochemical and transcriptional assays to investigate the selective targeting of the CBP/β-catenin interaction in conjunction with global transcriptional profiling to compare the three small molecules, ICG-001, C82, and E7386.
RESULT
Our data cast significant doubt that the mechanism of action of E7386 is via specific CBP/β-catenin antagonism.
CONCLUSION
It can thus be concluded that E7386 is not a specific CBP/β-catenin antagonist.
背景和目的
首个经临床评估的 CBP/β-连环蛋白拮抗剂 PRI-724 以静脉内持续输注的方式给药，具有出色的安全性。卫材公司最近公布了第三代口服可用的据称是 CBP/β-连环蛋白拮抗剂 E7386。然而，E7386 的几个结构特征和报道的细胞毒性对特定的 CBP/β-连环蛋白拮抗剂来说是出乎意料的。因此，我们对 E7386 与高度特异性的真正的 CBP/β-连环蛋白拮抗剂 ICG-001 和 C82（源自前药 PRI-724 的活性药物）进行了比较。
介绍
CBP/β-连环蛋白拮抗剂可重新平衡 CBP/β-连环蛋白和 p300/β-连环蛋白依赖性转录之间的平衡，并可能通过维持体干细胞池和调节与分化和免疫细胞功能相关的线粒体功能和代谢来治疗或预防许多衰老相关疾病。特异性 CBP/β-连环蛋白拮抗剂 ICG-001 和第二代化合物 C82（源自前药 PRI-724 的活性药物）的安全性、疗效和治疗潜力已在多种临床前疾病模型和肿瘤学及肝纤维化临床中得到广泛研究。然而，口服生物利用度的缺乏阻碍了 PRI-724 的进一步开发。因此，卫材公司最近提出了第三代口服可用的据称是 CBP/β-连环蛋白拮抗剂 E7386。在这里，我们对 E7386 与高度特异性的真正的 CBP/β-连环蛋白拮抗剂 ICG-001 和 C82 进行了比较分析。
方法
我们利用一系列先前验证的生化和转录测定来研究 CBP/β-连环蛋白相互作用的选择性靶向，并结合全转录组谱分析来比较这三种小分子 ICG-001、C82 和 E7386。
结果
我们的数据对 E7386 的作用机制是否通过特异性 CBP/β-连环蛋白拮抗作用产生表示严重怀疑。
结论
因此，可以得出结论，E7386 不是特异性的 CBP/β-连环蛋白拮抗剂。
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