2. Academic Validation
  3. I-8, a novel inhibitor of mutant IDH1, inhibits cancer progression in vitro and in vivo

I-8, a novel inhibitor of mutant IDH1, inhibits cancer progression in vitro and in vivo

  • Eur J Pharm Sci. 2019 Dec 1;140:105072. doi: 10.1016/j.ejps.2019.105072.
Panli Jia 1,  Yao Wu 1,  Hongzhi Du 2,  Lijun Yang 3,  Zhibo Zhang 1,  Tianfang Ma 3,  Sun Li 1,  Shengtao Yuan 4,  Ligong Lu 5,  Xiaoming Zha 6
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
  • 2 School of Pharmacy, Hubei University of Chinese Medicine, Hubei, China.
  • 3 Department of Pharmaceutical Engineering and Department of Biochemical Engineering, China Pharmaceutical University, Nanjing, China.
  • 4 Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China. Electronic address: yuanst@cpu.edu.cn.
  • 5 Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China. Electronic address: luligong1969@126.com.
  • 6 Department of Pharmaceutical Engineering and Department of Biochemical Engineering, China Pharmaceutical University, Nanjing, China. Electronic address: xmzha@cpu.edu.cn.
PMID: 31518680 DOI: 10.1016/j.ejps.2019.105072
Abstract

Isocitrate dehydrogenase 1 mutations have been discovered in an array of hematologic malignancies and solid tumors. These mutations could cause the production of high levels of 2-hydroxyglutarate, which in turn implicated in epigenetic changes and impaired cell differentiation. Here, we described the characterization of compound I-8, a novel mutant IDH1 Inhibitor, both in vitro and in vivo. Compound I-8 specifically inhibited 2-HG production, reduced histone methylation levels, induced differentiation and depleted stem characteristics in engineered and endogenous IDH1 mutant cells. In addition, oral administration of I-8 also significantly suppressed 2-HG production and histone methylation with dose of 150 mg/kg. And I-8 treatment also could induce differentiation and attenuate stem characteristics in tumor tissue. Together, these studies indicated that compound I-8 has clinical potential in tumor therapies as a effective mutant IDH1 Inhibitor, and provided scientific guidance for the development of mutant IDH1 Inhibitor in the future.

Keywords

2-Hydroxyglutarate; Compound I-8; Differentiation; Histone methylation; Isocitrate dehydrogenase 1; Mutant IDH1 inhibitor.

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