2. Academic Validation
  3. Discovery of novel glutaminase 1 allosteric inhibitor with 4-piperidinamine linker and aromatic heterocycles

Discovery of novel glutaminase 1 allosteric inhibitor with 4-piperidinamine linker and aromatic heterocycles

  • Eur J Med Chem. 2022 Jun 5;236:114337. doi: 10.1016/j.ejmech.2022.114337.
Xi Xu 1,  Xiujin Chang 1,  Jingxuan Huang 1,  Di Zhang 1,  Min Wang 1,  Tian Jing 1,  Yu Zhuang 1,  Junping Kou 2,  Zhixia Qiu 1,  Jubo Wang 1,  Zhiyu Li 3,  Jinlei Bian 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 2 State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medical, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: zhiyuli@cpu.edu.cn.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: bianjl@cpu.edu.cn.
PMID: 35428013 DOI: 10.1016/j.ejmech.2022.114337
Abstract

Glutaminase 1 (GLS1) is overexpressed in multiple types of malignant tumors and is viewed as a promising target in Cancer therapy. Thus, the discovery for small-molecule GLS1 inhibitors is being urgent. Based on our previous study of C147, a potent GLS1 allosteric inhibitor yet with a limited metabolic stability, a structure-based optimization was carried out, with a series of novel GLS1 allosteric inhibitors rationally designed, synthesized and biologically evaluated. Such endeavor has culminated in the identification of 41e, a promising GLS1 allosteric inhibitor with 4-piperidinamine linker and aromatic heterocycles. 41e displayed robust GLS1 binding affinity, superior liver microsome metabolic stability, and moderate anti-tumor activity (TGI: 47.5%) in HCT116 xenograft model with no considerable toxicity in vivo. The mechanism underlying the anti-proliferative effect of 41e on HCT116 cells was studied, revealing that the compound blocked the glutamine metabolism, induced the production of ROS, and triggered Apoptosis. These findings merit further investigation of 41e as a targeted Cancer therapeutic.

Keywords

4-Piperidinamine; Allosteric inhibitors; GLS1; Glutaminase 1; Glutamine metabolism.

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