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  3. Design, synthesis, and biological evaluation of novel glutaminase 1 allosteric inhibitors with an alkane chain tail group

Design, synthesis, and biological evaluation of novel glutaminase 1 allosteric inhibitors with an alkane chain tail group

  • Eur J Med Chem. 2023 Jan 15;246:115014. doi: 10.1016/j.ejmech.2022.115014.
Xiujin Chang 1,  Min Wang 1,  Di Zhang 1,  Yuqing Zhang 1,  Jubo Wang 2,  Zhiyu Li 1,  Jinlei Bian 3,  Xi Xu 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: [email protected].
  • 3 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: [email protected].
  • 4 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: [email protected].
PMID: 36525694 DOI: 10.1016/j.ejmech.2022.115014
Abstract

Tumor cells often exhibit metabolic reprogramming to maintain their rapid growth and proliferation. Glutaminase 1 (GLS1) has been viewed as a promising target in the glutamine metabolism pathway for the treatment of malignant tumors. Using structure-based drug design approaches, a novel series of GLS1 allosteric inhibitors were designed and synthesized. Compound 41a (LWG-301) with an alkane chain "tail" group had potent biochemical and cellular GLS1 activity, and improved metabolic stability. LWG-301 exhibited moderate antitumor effects in HCT116 xenograft model, with TGI of 38.9% in vivo. Mechanistically, LWG-301 could significantly block glutamine metabolism, resulting in changes in the corresponding amino acid levels in cells, induce a concentration-dependent increase in intracellular ROS levels, and induce Apoptosis. Taken together, this paper provides more structural references and new design strategy for the development of GLS1 allosteric inhibitors.

Keywords

Allosteric inhibitors; Glutaminase 1; Glutamine metabolism.

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