Discovery of 5-phenyl-3-ureidothiophene-2-carboxamides as protective agents for ALS patient iPSC-derived motor neurons

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-03 DOI:10.1016/j.bmcl.2024.129935

Haruhiko Hattori, Kazuya Osumi, Masamichi Tanaka, Tadamasa Arai, Kazumi Nishimura, Naoyoshi Yamamoto, Keiko Sakamoto, Yasufumi Goto, Yuji Sugawara

引用次数: 0

Abstract

We discovered novel neuroprotective compounds by phenotypic screening using SOD1-mutant amyotrophic lateral sclerosis (ALS) patient induced pluripotent stem cell (iPSC)-derived motor neurons. Mechanistic analysis showed that the protective effect of initial hit compound 1 was likely due to the inhibition of MAP4Ks, including MAP4K4, a member of the MAP4K kinase family. Structural transformation led to compound 15f, which showed improved MAP4K4 inhibitory activity and superior neuroprotective effects compared to 1 in motor neurons. The results suggest that structural optimization based on MAP4K4 inhibitory activity might improve the neuroprotective effect of this series of compounds.

Abstract Image

查看原文本刊更多论文

发现 5-苯基-3-脲基噻吩-2-羧酰胺作为 ALS 患者 iPSC 衍生运动神经元的保护剂。

我们利用SOD1突变型肌萎缩性侧索硬化症（ALS）患者诱导多能干细胞（iPSC）衍生的运动神经元，通过表型筛选发现了新型神经保护化合物。机理分析表明，最初命中的化合物 1 的保护作用可能是由于抑制了 MAP4K，包括 MAP4K 激酶家族的成员 MAP4K4。化合物 15f 在运动神经元中的 MAP4K4 抑制活性和神经保护效果均优于化合物 1。结果表明，基于 MAP4K4 抑制活性的结构优化可能会提高这一系列化合物的神经保护效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

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.