Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
Bioorg Med Chem Lett. 2024 Nov 15;113:129935. doi: 10.1016/j.bmcl.2024.129935. Epub 2024 Sep 3.
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.
我们通过使用 SOD1 突变型肌萎缩侧索硬化症 (ALS) 患者诱导多能干细胞 (iPSC) 衍生的运动神经元进行表型筛选，发现了新型神经保护化合物。机制分析表明，初始命中化合物 1 的保护作用可能是由于 MAP4Ks 的抑制，包括 MAP4K4，MAP4K 激酶家族的成员。结构转化导致化合物 15f 的产生，与 1 相比，它在运动神经元中显示出更好的 MAP4K4 抑制活性和优越的神经保护作用。结果表明，基于 MAP4K4 抑制活性的结构优化可能会提高该系列化合物的神经保护作用。
