E7386 is not a Specific CBP/β-Catenin Antagonist.

IF 2.9 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current molecular pharmacology Pub Date : 2024-01-01 DOI:10.2174/1874467217666230529114100

Yusuke Higuchi, Cu Nguyen, Nyam-Osor Chimge, Ching Ouyang, Jia-Ling Teo, Michael Kahn

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引用次数: 0

Abstract

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.

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E7386不是特异性CBP/β-Catenin拮抗剂。

背景和目的:首个临床评估的CBP/β-catenin拮抗剂PRI-724，通过静脉持续输注显示出极好的安全性。卫材最近公开了第三代口服CBP/β-catenin拮抗剂E7386。然而，E7386的一些结构特征和报道的细胞毒性对于特定的CBP/β-catenin拮抗剂来说是出乎意料的。因此，我们对E7386与高特异性的CBP/β-catenin拮抗剂ICG-001和C82进行了比较，ICG-001和C82是由前药PRI-724衍生的活性剂。CBP/β-catenin拮抗剂可以重新平衡CBP/β-catenin和p300/β-catenin依赖转录之间的平衡，可能通过维持体细胞干细胞库、调节线粒体功能和参与分化和免疫细胞功能的代谢来治疗或预防许多衰老疾病。特异性CBP/β-catenin拮抗剂ICG-001和第二代化合物C82(源自前药PRI-724的活性剂)的安全性、有效性和治疗潜力已在各种临床前疾病模型和肿瘤和肝纤维化临床中得到广泛研究。然而，缺乏口服生物利用度阻碍了PRI-724的进一步开发。因此，卫材最近提出了第三代口服CBP/β-catenin拮抗剂E7386。在这里，我们将E7386与高特异性的真正CBP/β-catenin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分析来研究CBP/β-catenin相互作用的选择性靶向性，并结合全局转录谱来比较三个小分子，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-catenin拮抗提出了重大质疑。结论:E7386不是特异性的CBP/β-catenin拮抗剂。

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来源期刊

Current molecular pharmacology Pharmacology, Toxicology and Pharmaceutics-Drug Discovery

CiteScore

4.90

自引率

3.70%

发文量

112

期刊介绍： Current Molecular Pharmacology aims to publish the latest developments in cellular and molecular pharmacology with a major emphasis on the mechanism of action of novel drugs under development, innovative pharmacological technologies, cell signaling, transduction pathway analysis, genomics, proteomics, and metabonomics applications to drug action. An additional focus will be the way in which normal biological function is illuminated by knowledge of the action of drugs at the cellular and molecular level. The journal publishes full-length/mini reviews, original research articles and thematic issues on molecular pharmacology. Current Molecular Pharmacology is an essential journal for every scientist who is involved in drug design and discovery, target identification, target validation, preclinical and clinical development of drugs therapeutically useful in human disease.