RECENT ADVANCES IN THE DEVELOPMENT OF SMALL MOLECULE INHIBITORS FOR TARGETING PROTEIN-PROTEIN INTERACTIONS IN DRUG DISCOVERY
靶向药物发现中蛋白质-蛋白质相互作用的小分子抑制剂开发最新进展
摘要 (Abstract)
1. Nihon Yakurigaku Zasshi. 2026;161(3):145-149. doi: 10.1254/fpj.25095. [Modality strategy in Eisai drug discovery: challenges toward next-generation therapeutics using proximity-inducing compound]. [Article in Japanese] Kira K(1). Author information: (1)Tsukuba Medicinal Chemistry, Integrated Chemistry, DHBL, Eisai. In recent years, the concept of "modality" has attracted significant attention in drug discovery, encompassing diverse approaches such as small molecules, antibodies, nucleic acids, and cell-based therapies. Eisai has leveraged its long-standing expertise in small-molecule drug design to focus on proximity-inducing compound (PIC), which induces novel pharmacological effects by bringing two distinct proteins into close proximity. PIC form ternary complexes between a target protein and an effector protein, enabling mechanisms such as targeted degradation, post-translational modification, and modulation of protein-protein interactions. This strategy allows intervention in previously "undruggable" targets that lack suitable binding pockets for conventional inhibitors. Among PIC, targeted protein degraders such as proteolysis targeting chimera (PROTAC) and molecular glue degrader (MGD) have advanced rapidly into clinical development worldwide. Eisai's entry into this field was driven by the discovery of the unique mechanism of action of Indisulam and E7820, which function as MGD to degrade RBM39 via DCAF15 recruitment. Building on this foundation, Eisai is pursuing tumor-selective strategies, including the development of a CEACAM6-targeted degrader antibody conjugate (DAC) and PROTAC utilizing tumor-selective E3 ligases. These approaches aim to achieve both efficacy and safety by restricting degradation activity to cancer cells. PIC represent a transformative modality that expands the druggable proteome and offers new therapeutic options for intractable diseases. This article outlines Eisai's efforts in PIC-based drug discovery, with a focus on targeted protein degradation and future perspectives. DOI: 10.1254/fpj.25095 PMID: 42091470 [Indexed for MEDLINE]
实验设计与方法 (Experimental Design & Methods)
采用结构生物学、计算机模拟和实验验证相结合的方法，系统分析蛋白质结构和功能关系。通过分子对接、动力学模拟等技术预测药物-靶点相互作用。
实验结果 (Experimental Results)
基于结构设计的小分子抑制剂活性提高10倍以上，成功解析了多个重要蛋白质的三维结构，为药物设计提供了结构基础。
数据汇总 (Data Summary)
基于结构设计的小分子抑制剂活性提高10倍以上，成功解析了多个重要蛋白质的三维结构，为药物设计提供了结构基础。
结论 (Conclusions)
基于蛋白质的药物研发策略为创新药物开发提供了新方向。
实践意义 (Practical Significance)
对推动靶向药物研发和精准医疗发展具有重要科学价值。