The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer.
10.1016/j.apsb.2022.12.019
- Author:
Yang LIU
1
;
Wei XU
2
;
Mingxue LI
1
;
Yueying YANG
1
;
Dejuan SUN
1
;
Lidian CHEN
3
;
Hua LI
1
;
Lixia CHEN
1
Author Information
1. Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
2. Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
3. The Institute of Rehabilitation Industry, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
- Publication Type:Review
- Keywords:
Cancer;
D-2HG;
Epigenetics;
IDH1;
IDH1 inhibitors;
Immune microenvironment;
Metabolic reprogramming;
Regulatory mechanisms
- From:
Acta Pharmaceutica Sinica B
2023;13(4):1438-1466
- CountryChina
- Language:English
-
Abstract:
Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.
