Targeting glutaminase 1 (GLS1) by small molecules for anticancer therapeutics

Eur J Med Chem. 2023 Apr 5:252:115306. doi: 10.1016/j.ejmech.2023.115306.

Yangyang Chen ¹, Lun Tan ¹, Jing Gao ¹, Congcong Lin ², Fengbo Wu ³, Yang Li ⁴, Jifa Zhang ⁵

Affiliations

1 Joint Research Institution of Altitude Health, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
2 Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
3 Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: [email protected].
4 Joint Research Institution of Altitude Health, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: [email protected].
5 Joint Research Institution of Altitude Health, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: [email protected].

PMID: 36996714 DOI: 10.1016/j.ejmech.2023.115306

Abstract

Glutaminase-1 (GLS1) is a critical enzyme involved in several cellular processes, and its overexpression has been linked to the development and progression of Cancer. Based on existing research, GLS1 plays a crucial role in the metabolic activities of Cancer cells, promoting rapid proliferation, cell survival, and immune evasion. Therefore, targeting GLS1 has been proposed as a promising Cancer therapy strategy, with several GLS1 inhibitors currently under development. To date, several GLS1 inhibitors have been identified, which can be broadly classified into two types: active site and allosteric inhibitors. Despite their pre-clinical effectiveness, only a few number of these inhibitors have advanced to initial clinical trials. Hence, the present medical research emphasizes the need for developing small molecule inhibitors of GLS1 possessing significantly high potency and selectivity. In this manuscript, we aim to summarize the regulatory role of GLS1 in physiological and pathophysiological processes. We also provide a comprehensive overview of the development of GLS1 inhibitors, focusing on multiple aspects such as target selectivity, in vitro and in vivo potency and structure-activity relationships.

Keywords

Glutaminase-1; Small-molecule inhibitors; Structure-activity relationships (SARs); X-ray co-crystal structure analyses.

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