Abstract：
Mutations in IDH1 are commonly observed across various cancers, causing the conversion of α-KG to 2-HG. Elevated levels of 2-HG disrupt histone and DNA demethylation processes, promoting tumor development. Consequently, there is substantial interest in developing small molecule inhibitors targeting the mutant enzymes. Herein, we report a structure-based high-throughput virtual screening strategy using a natural products library, followed by hit-to-lead optimization. Through this process, we discover a potent compound, named 11s, which exhibited significant inhibition to IDH1 R132H and IDH1 R132C with IC50 values of 124.4 and 95.7 nM, respectively. Furthermore, 11s effectively reduced 2-HG formation, with EC50 values of 182 nM in U87 R132H cell, and 84 nM in HT-1080 cell. In addition, 11s significantly reduced U87 R132H and HT-1080 cell proliferation with GC50 values of 3.48 and 1.38 μM, respectively. PK-PD experiments further confirmed that compound 11s significantly decreased 2-HG formation in an HT-1080 xenograft mouse model, resulting in notable suppression of tumor growth without apparent loss in body weight.
摘要：
IDH1的突变通常在各种癌症中观察到，导致α-KG转换为2-HG。2-HG水平升高会破坏组蛋白和DNA去甲基化过程，促进肿瘤发展。因此,对开发靶向突变酶的小分子抑制剂有很大的兴趣。在这里，我们报告了使用天然产物库的基于结构的高通量虚拟筛选策略，其次是命中领先优化。通过这个过程,我们发现了一种有效的化合物，名为11s，对IDH1R132H和IDH1R132C表现出显著的抑制作用，IC50值分别为124.4和95.7nM，分别。此外，11s有效地减少了2-HG的形成，在U87R132H细胞中EC50值为182nM，和84nM在HT-1080细胞中。此外,11s显着降低U87R132H和HT-1080细胞增殖，GC50值为3.48和1.38μM，分别。PK-PD实验进一步证实，化合物11s显着降低HT-1080异种移植小鼠模型中2-HG的形成，导致肿瘤生长的显著抑制，而体重没有明显下降。
