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
  • 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: [email protected].
  • 5. Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China. Electronic address: [email protected].
  • 6. Department of Pharmaceutical Engineering and Department of Biochemical Engineering, China Pharmaceutical University, Nanjing, China. Electronic address: [email protected].
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.
Products