Design, synthesis, and evaluation of a novel protein degrader FPFT-2216

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-03-22 DOI:10.1016/j.bmcl.2025.130193

Yasuyuki Ueda, Takashi Ando, Yoshiteru Eikyu, Takumi Okamoto, Hironori Yokoyama, Naoshi Kunimura, Daiki Kanaoka, Shotaro Izuno, Mayumi Watanabe

引用次数: 0

Abstract

For multiple myeloma (MM), various modalities of therapeutic drugs have been approved in recent years, and treatment outcomes for MM have greatly improved, but unmet medical needs still exist and new therapeutic drugs are needed. With the aim of developing a therapeutic drug for MM that has a scaffold different from the protein degrader immunomodulatory drugs (IMiDs), exploratory research was performed using the highly useful Huisgen cycloaddition reaction, and a novel lead compound 3-(4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione (FPFT-2127) was discovered. Optimization studies identified FPFT-2216, which exhibited stronger antitumor activity against MM than existing thalidomide derivatives. Furthermore, FPFT-2216 showed a synergistic combination effect with Daratumumab (Dara), a standard treatment for MM.

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新型蛋白质降解剂FPFT-2216的设计、合成和评价。

对于多发性骨髓瘤（multiple myeloma， MM），近年来已批准了多种形式的治疗药物，MM的治疗效果也有了很大改善，但仍存在未满足的医疗需求，需要新的治疗药物。为了开发一种具有不同于蛋白质降解免疫调节药物（IMiDs）支架的MM治疗药物，我们利用非常有用的Huisgen环加成反应进行了探索性研究，发现了一种新的先导化合物3-（4-（噻吩-3-基）- 1h -1,2,3-三唑-1-基）哌啶-2,6-二酮（FPFT-2127）。优化研究发现，与现有的沙利度胺衍生物相比，FPFT-2216具有更强的抗MM肿瘤活性。此外，FPFT-2216显示出与Daratumumab （Dara）的协同联合效应，Dara是MM的标准治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.