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Review
. 2022 Aug 24:13:982424.
doi: 10.3389/fphar.2022.982424. eCollection 2022.

Recent advances of IDH1 mutant inhibitor in cancer therapy

Wangqi Tian  1 , Weitong Zhang  1 , Yifan Wang  1 , Ruyi Jin  1 , Yuwei Wang  1 , Hui Guo  1 , Yuping Tang  1 , Xiaojun Yao  2
Affiliations
Review

Recent advances of IDH1 mutant inhibitor in cancer therapy

Wangqi Tian et al. Front Pharmacol. .

Abstract

Isocitrate dehydrogenase (IDH) is the key metabolic enzyme that catalyzes the conversion of isocitrate to α-ketoglutarate (α-KG). Two main types of IDH1 and IDH2 are present in humans. In recent years, mutations in IDH have been observed in several tumors, including glioma, acute myeloid leukemia, and chondrosarcoma. Among them, the frequency of IDH1 mutations is higher than IDH2. IDH1 mutations have been shown to increase the conversion of α-KG to 2-hydroxyglutarate (2-HG). IDH1 mutation-mediated accumulation of 2-HG leads to epigenetic dysregulation, altering gene expression, and impairing cell differentiation. A rapidly emerging therapeutic approach is through the development of small molecule inhibitors targeting mutant IDH1 (mIDH1), as evidenced by the recently approved of the first selective IDH1 mutant inhibitor AG-120 (ivosidenib) for the treatment of IDH1-mutated AML. This review will focus on mIDH1 as a therapeutic target and provide an update on IDH1 mutant inhibitors in development and clinical trials.

Keywords: 2-HG; hypermethylation; isocitrate dehydrogenase mutation; mIDH1 inhibitors; natural product.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The structure of IDH1 and the distribution of various domains.
FIGURE 2
FIGURE 2
The molecular mechanism of IDH1 mutation (A) and corresponding structure of substrate (B).
FIGURE 3
FIGURE 3
(A) The structure of phenyl-glycine compounds. (B) The binding mode of Indane analogs with mIDH1 R132H. (C) The structure of 3-pyrimidin-4-yl-oxazolidin-2-ones. (D) The binding mode of IDH305 with mIDH1 R132H.
FIGURE 4
FIGURE 4
(A,B) The structure of AG-881 and binding mode with mIDH1. (C,D) The structure of BAY1436032 and binding mode with mIDH1. (E,F) The structure of compound 6 and binding mode with mIDH1. (G,H) The structure of VVS and binding mode with mIDH1. (I,J) The structure of GSK321 and binding mode with mIDH1.
FIGURE 5
FIGURE 5
The structure of DS-1001b (A) and binding mode with mIDH1 (B).
FIGURE 6
FIGURE 6
The structure of compound 7–12 (A) and binding mode with mIDH1 (B).
FIGURE 7
FIGURE 7
(A,B) The structure of SYC-435 and binding mode with mIDH1. (C) The structure of aromatic sulfonamide compounds. (D,E) The structure of Compound 13 and binding mode with mIDH1.
FIGURE 8
FIGURE 8
(A) The structure of BRD2879. (B) The structure of compound 14. (C,D) The structure of HMS-101and binding mode with mIDH1. (E) The structure of 2-(3-(trifluoromethyl) phenyl) isothiazol-3(2H)-one. (F) The structure of Clomifene citrate. (G,H) The structure of DC_H31 and binding mode with mIDH1. (I,J) The structure of WM17 and binding mode with mIDH1.
FIGURE 9
FIGURE 9
(A,B) The structure of CRUK-MI and binding mode with mIDH1. (C,D) The structure of ZX-06 and binding mode with mIDH1.
FIGURE 10
FIGURE 10
(A) The structure of L806-0255, V015-1671, AQ-714/41674992, and binding mode with mIDH1. (B) The structure of KRC-09. (C) The structure of Steroids. (D) The structure of licochalone (A)
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