In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 495-495
Abstract:
Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are critical enzymes of the tricarboxylic acid cycle, which convert isocitrate into α-ketoglutarate (α-KG). IDH1 or IDH2 mutations are observed in more than 80% of low- to mid-grade gliomas and in ~20% of acute myeloid leukemia (AML). Tumor-related IDH1/2 mutants acquire a novel function of using α-KG as a substrate to produce R-2-hydroxyglutarate (2-HG). 2-HG is an oncogenic metabolite, and reducing it by inhibiting mutant IDH1 or IDH2 has been shown to be an effective treatment approach. Although agents targeting IDH1 or IDH2 have been approved to treat IDH-mutant cancers, existing IDH1 inhibitors do not cross the blood-brain barrier, a feature needed for treating glioma. Furthermore, resistant mutations do occur, including cross-isoform mutations, which call for the development of dual IDH1/2 inhibitors with good brain penetration. However, IDH1/2 dual inhibitors are rarely discovered. Here we report the discovery of BPI-221351, a potent inhibitor of mutant IDH1 and mutant IDH2. BPI-221351 shows excellent inhibitory activities against both IDH1 and IDH2 enzymes, and potently suppresses 2-HG levels in tumor cells harboring IDH1 or IDH2 mutants. In an IDH-mutant xenograft model, BPI-221351 reduced 2-HG to baseline level up to 24 h after a single oral dose administration. In addition, BPI-221351 possesses excellent blood-brain-barrier penetration with a higher drug concentration in the brain than that in plasma. In conclusion, BPI-221351 exhibits strong activity towards both IDH1 and IDH2 mutants in vitro and in vivo with favorable pharmacological properties, presenting a new therapeutic opportunity for treating glioma and other relevant cancers. Citation Format: Hongling Shen, Xiaofeng Xu, Yabin Li, Xizhen Song, Jie Chen, Yunting Bi, Jing Guo, Tong Xu, Huijuan Zhang, Lijia Liu, Zhengyao Zou, Jialin Ren, Jun Tong, Xiaoyun Liu, Hongfei Rong, Teng Ma, Chao Wang, Xiangyong Liu, Hong Chen, Jiayu Zhao, Xuepeng Ju, Haibo Chen, Haidi Shen, Hong Lan, Lieming Ding, Jiabing Wang. Discovery of BPI-221351, a potent, selective, orally available, and brain penetrating dual inhibitor of mutant IDH1/2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 495.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2023-495
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2023
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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