Design, synthesis, and biological evaluation of novel glutaminase 1 allosteric inhibitors with an alkane chain tail group.
Eur J Med Chem
; 246: 115014, 2023 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-36525694
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Glutaminase
/
Glutamina
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article