Recent advances in the development of sialyltransferase inhibitors to control cancer metastasis: A comprehensive review.

Autor: Al Saoud R; Pharmaceutical Sciences Program, College of Pharmacy, Al Ain University, P.O. Box 112612, Al Ain, Abu Dhabi, United Arab Emirates; AAU Health and Biomedical Research Center, Al Ain University, P.O. Box 112612, Abu Dhabi, United Arab Emirates., Hamrouni A; Pharmaceutical Sciences Program, College of Pharmacy, Al Ain University, P.O. Box 112612, Al Ain, Abu Dhabi, United Arab Emirates; AAU Health and Biomedical Research Center, Al Ain University, P.O. Box 112612, Abu Dhabi, United Arab Emirates., Idris A; School of Biomedical Sciences, Queensland University of Technology, Gardens Point, QLD, Australia; School of Pharmacy and Medical Science, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia., Mousa WK; Pharmaceutical Sciences Program, College of Pharmacy, Al Ain University, P.O. Box 112612, Al Ain, Abu Dhabi, United Arab Emirates; AAU Health and Biomedical Research Center, Al Ain University, P.O. Box 112612, Abu Dhabi, United Arab Emirates., Abu Izneid T; Pharmaceutical Sciences Program, College of Pharmacy, Al Ain University, P.O. Box 112612, Al Ain, Abu Dhabi, United Arab Emirates; AAU Health and Biomedical Research Center, Al Ain University, P.O. Box 112612, Abu Dhabi, United Arab Emirates. Electronic address: tareq.abuizneid@aau.ac.ae.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Sep; Vol. 165, pp. 115091. Date of Electronic Publication: 2023 Jul 06.
DOI: 10.1016/j.biopha.2023.115091
Abstrakt: Metastasis accounts for the majority of cancer-associated mortalities, representing a huge health and economic burden. One of the mechanisms that enables metastasis is hypersialylation, characterized by an overabundance of sialylated glycans on the tumor surface, which leads to repulsion and detachment of cells from the original tumor. Once the tumor cells are mobilized, sialylated glycans hijack the natural killer T-cells through self-molecular mimicry and activatea downstream cascade of molecular events that result in inhibition of cytotoxicity and inflammatory responses against cancer cells, ultimately leading to immune evasion. Sialylation is mediated by a family of enzymes known as sialyltransferases (STs), which catalyse the transfer of sialic acid residue from the donor, CMP-sialic acid, onto the terminal end of an acceptor such as N-acetylgalactosamine on the cell-surface. Upregulation of STs increases tumor hypersialylation by up to 60% which is considered a distinctive hallmark of several types of cancers such as pancreatic, breast, and ovarian cancer. Therefore, inhibiting STs has emerged as a potential strategy to prevent metastasis. In this comprehensive review, we discuss the recent advances in designing novel sialyltransferase inhibitors using ligand-based drug design and high-throughput screening of natural and synthetic entities, emphasizing the most successful approaches. We analyse the limitations and challenges of designing selective, potent, and cell-permeable ST inhibitors that hindered further development of ST inhibitors into clinical trials. We conclude by analysing emerging opportunities, including advanced delivery methods which further increase the potential of these inhibitors to enrich the clinics with novel therapeutics to combat metastasis.
Competing Interests: Declaration of Competing Interest None.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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