Discovery of aminothiazole derivatives as a chemical scaffold for glutaminase inhibition

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Costa, Renna K. E. ; Brancaglion, Guilherme A. ; Pinheiro, Matheus P. ; Adamoski, Douglas ; da Silva, Bianca N. ; Negrao, Cyro Z. de V. ; Goncalves, Kaliandra de A. ; Rodrigues, Camila T. ; Ambrosio, Andre L. B. ; Guido, Rafael V. C. ; Pastre, Julio C. ; Dias, Sandra M. G.

• Document type: Journal article
• Source: RESULTS IN CHEMISTRY; v. 5, p. 17-pg., 2023-02-17.

Abstract

Cancer cells rely on different mechanisms to maintain their dysregulated metabolism and high proliferation. Metabolic rewiring with an increased dependency on glutamine, the most abundant amino acid in the blood, is a common feature of several types of cancers, including triple-negative breast cancer (TNBC). The enzyme glutaminase (GLS) converts glutamine to glutamate, a reaction that provides alpha-ketoglutarate for the tricarbox-ylic/citric acid cycle (TCA) and chromatin-modifying enzymes, thus impacting proliferation and cell differen-tiation. Glutamine metabolism also impacts the redox balance and synthesis of nucleotides, lipids, and other amino acids. Glutaminase is a potential therapeutic target for cancer, with inhibitors in clinical trials. We pre-viously performed high-throughput screening (HTS) to look for GLS inhibitors. Here, we present the structur-e-activity relationship (SAR) study of one of the hits, C12, a molecule containing the heteroaromatic nucleus 2-amino-thiazole. The SAR investigation was carried out through modifications of the substituents from the main 3 rings present at the C12 prototype, rings A-C. The combination of 4-F and phenylacetic substitutions on ring A, the incorporation of a 1,3,4-thiadiazole moiety on ring B, and a 4-CN substituent on ring C were the best options to improve specific GLS inhibition. In this series, three compounds exhibited suitable enzyme (GAC vs GLS2) and cell (MDA-MB-231 vs SKBR3) selectivity and, thus, could be useful for the development of new glutaminase inhibitors. (AU)

• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 16/09077-4 - Developing new glutaminase inhibitors with potential anti-tumor activity
• Grantee: Renna Karoline Eloi Costa
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 21/13736-1 - Functional impact of the glutaminase enzyme interaction with pyruvate kinase M2 in the tumor microenvironment
• Grantee: Bianca Novaes da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 14/26378-2 - Development of methodologies and synthetic processes employing a new technological platform: micro and meso reactor assisted synthesis of natural products and derivatives with potential pharmacological activity
• Grantee: Júlio Cezar Pastre
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 19/16351-3 - The glutaminase role on tumor progression
• Grantee: Sandra Martha Gomes Dias
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/12904-5 - Discovery of Plasmodium falciparum inhibitors from Cerrado plants as lead compounds candidates for malaria: integrated studies of ultra-efficient chromatography, spectroscopy, and biological assays
• Grantee: Rafael Victorio Carvalho Guido
• Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants
• FAPESP's process: 21/06661-5 - Enabling technologies for the sustainable chemical synthesis of platform molecules, new chemicals and bioactive compounds
• Grantee: Júlio Cezar Pastre
• Support Opportunities: Program for Research on Bioenergy (BIOEN) - Young Investigators Grants - Phase 2
• FAPESP's process: 14/15968-3 - Understanding the glutaminase functional regulation and the development of inhibitors as new approaches to cancer therapy
• Grantee: Sandra Martha Gomes Dias
• Support Opportunities: Regular Research Grants