State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medcial University, Guiyang 550014, China.
School of Pharmacy, Nanchang University, Nanchang 330006, China.
Bioorg Med Chem Lett. 2020 Jan 15;30(2):126825. doi: 10.1016/j.bmcl.2019.126825. Epub 2019 Nov 30.
IDH1 mutations are closely related to the development and progression of various human cancers, such as glioblastoma, sarcoma, and acute myeloid leukemia. By screening dozens of reported natural compounds using both wild-type and mutant IDH1 enzymatic assays, we discovered Licochalcone A is a selective inhibitor to the R132C-mutant IDH1 with an IC value of 5.176 μM, and inhibits the proliferation of sarcoma HT-1080 cells with an IC value of 10.75 μM. Suggested by the molecular docking results, Licochalcone A might occupy the allosteric pocket between the two monomers of IDH1 homodimer, and the R132H mutation was unfavorable for the binding of Licochalcone A with the IDH1 protein, as compared to the R132C mutation. Revealed by the RNA-Seq data analysis, the Cell Cycle pathway was the most over-represented pathway for HT-1080 cells treated with Licochalcone A. Consistent with these results, Licochalcone A induced apoptosis and cell cycle arrest of HT-1080 cells, while it showed minimal effect against the proliferation of normal RCTEC cells. The discovery of Licochalcone A as a mutation-selective IDH1 inhibitor can serve as a promising starting point for the development of mutation-selective anti-tumor lead compounds targeting IDH1.
IDH1 突变与各种人类癌症的发展和进展密切相关，如脑胶质瘤、肉瘤和急性髓系白血病。通过使用野生型和突变型 IDH1 酶促测定法筛选数十种报道的天然化合物，我们发现甘草查尔酮 A 是 R132C 突变 IDH1 的选择性抑制剂，IC 值为 5.176 μM，并抑制肉瘤 HT-1080 细胞的增殖，IC 值为 10.75 μM。根据分子对接结果推测，甘草查尔酮 A 可能占据 IDH1 同源二聚体两个单体之间的变构口袋，与 R132C 突变相比，R132H 突变不利于甘草查尔酮 A 与 IDH1 蛋白的结合。通过 RNA-Seq 数据分析揭示，细胞周期途径是甘草查尔酮 A 处理的 HT-1080 细胞中过度表达的途径。与这些结果一致，甘草查尔酮 A 诱导 HT-1080 细胞凋亡和细胞周期停滞，而对正常 RCTEC 细胞的增殖影响很小。发现甘草查尔酮 A 作为突变选择性 IDH1 抑制剂，可以作为开发针对 IDH1 的突变选择性抗肿瘤先导化合物的有希望的起点。
