Challenges for the development of mutant isocitrate dehydrogenases 1 inhibitors to treat glioma

Eur J Med Chem. 2023 Sep 5:257:115464. doi: 10.1016/j.ejmech.2023.115464.

Qing-Xin Wang ¹, Peng-Yu Zhang ², Qing-Qing Li ¹, Zhen-Jiang Tong ¹, Jia-Zhen Wu ¹, Shao-Peng Yu ¹, Yan-Cheng Yu ¹, Ning Ding ¹, Xue-Jiao Leng ¹, Liang Chang ¹, Jin-Guo Xu ¹, Shan-Liang Sun ³, Ye Yang ⁴, Nian-Guang Li ⁵, Zhi-Hao Shi ⁶

Affiliations

1 National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu, 210023, China.
2 School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu, 611731, China.
3 National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu, 210023, China. Electronic address: [email protected].
4 School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China. Electronic address: [email protected].
5 National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu, 210023, China. Electronic address: [email protected].
6 Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu, 211198, China. Electronic address: [email protected].

PMID: 37235998 DOI: 10.1016/j.ejmech.2023.115464

Abstract

Glioma is one of the most common types of brain tumors, and its high recurrence and mortality rates threaten human health. In 2008, the frequent isocitrate dehydrogenase 1 (IDH1) mutations in glioma were reported, which brought a new strategy in the treatment of this challenging disease. In this perspective, we first discuss the possible gliomagenesis after IDH1 mutations (mIDH1). Subsequently, we systematically investigate the reported mIDH1 inhibitors and present a comparative analysis of the ligand-binding pocket in mIDH1. Additionally, we also discuss the binding features and physicochemical properties of different mIDH1 inhibitors to facilitate the future development of mIDH1 inhibitors. Finally, we discuss the possible selectivity features of mIDH1 inhibitors against WT-IDH1 and IDH2 by combining protein-based and ligand-based information. We hope that this perspective can inspire the development of mIDH1 inhibitors and bring potent mIDH1 inhibitors for the treatment of glioma.

Keywords

Glioma; Selectivity; Structure-based; mIDH1.

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