Licochalcone A suppresses the proliferation of sarcoma HT-1080 cells, as a selective R132C mutant IDH1 inhibitor

Bioorg Med Chem Lett. 2020 Jan 15;30(2):126825. doi: 10.1016/j.bmcl.2019.126825.

Chujiao Hu ¹, Yu Zuo ², Jingqiu Liu ³, Heng Xu ³, Weike Liao ¹, Yongjun Dang ⁴, Cheng Luo ³, Lei Tang ⁵, Hao Zhang ⁶

Affiliations

1 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medcial University, Guiyang 550014, China.
2 School of Pharmacy, Nanchang University, Nanchang 330006, China.
3 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
4 School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
5 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medcial University, Guiyang 550014, China. Electronic address: tlei1974@163.com.
6 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: hao_cadd@simm.ac.cn.

PMID: 31836442 DOI: 10.1016/j.bmcl.2019.126825

Abstract

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 IC₅₀ value of 5.176 μM, and inhibits the proliferation of sarcoma HT-1080 cells with an IC₅₀ 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.

Keywords

Licochalcone A; Mutant IDH1; Selective inhibitor.

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