Sialyltransferase Inhibitors for the Treatment of Cancer Metastasis: Current Challenges and Future Perspectives

Abstract

Potent, cell-permeable, and subtype-selective sialyltransferase inhibitors represent an attractive family of substances that can potentially be used for the clinical treatment of cancer metastasis. These substances operate by specifically inhibiting sialyltransferase-mediated hypersialylation of cell surface glycoproteins or glycolipids, which then blocks the sialic acid recognition pathway and leads to deterioration of cell motility and invasion. A vast amount of evidence for the in vitro and in vivo effects of sialyltransferase inhibition or knockdown on tumor progression and tumor cell metastasis or colonization has been accumulated over the past decades. In this regard, this review comprehensively discusses the results of studies that have led to the recent discovery and development of sialyltransferase inhibitors, their potential biomedical applications in the treatment of cancer metastasis, and their current limitations and future opportunities.

Small molecule inhibitors of mammalian glycosylation

“…This class of molecules was pioneered two decades ago by Richard Schmidt [183] , [184] . These molecules were designed based on the observation that sialyltransferase-catalysed reactions of the donor substrate CMP-Neu5Ac exhibit a transition state where CMP leaves prior to bond formation with the hydroxyl group of the nucleophile [185] . By mimicking this transition state, CMP-Neu5Ac analogues can inhibit sialyltransferase activity.…”

“…Cytidine analogues have also been developed [185] . Among them is 2′- O -methyl-CMP which demonstrated polysialyltransferase inhibitory effects.…”

The Distinct Roles of Sialyltransferases in Cancer Biology and Onco-Immunology

“…Moreover, limitations of methodological approaches need to be considered, such as missing environmental context for in vitro cell cultures or species differences for in vivo studies. Functional redundancy may exist between SiaTs, and while specific small-molecule SiaT inhibitors that bind and block select SiaTs may hold promise for therapeutic and diagnostic use [for recent reviews see (257)(258)(259)], combination strategies might be needed in a given context. However, the observation that SiaTs are responsible for the generation of glyco-immune checkpoints has reinvigorated ambitions of researchers to explore the role of individual SiaTs in cancer, which may pave the way for novel immune normalization (260), and more personalized, cancer immunotherapies.…”

Sialyltransferases and Neuraminidases: Potential Targets for Cancer Treatment

“…Sialyltransferases and their sialylation processes serve as potentially important targets in strategies designed to identify and develop treatments for cancer metastasis, given the substantial body of biological evidence that they are connected with tumor progression, adhesion, and migration in human cancer cells [ 2 ].…”

“…According to a study conducted in the US, the number of cancer incidence cases is to be increased by 50% by 2050, and hence there needs to be a greater emphasis on the development of alternative therapies [ 1 ] Though the existing cancer treatments such as chemotherapy, immunotherapy, and early detection and prevention strategies have majorly contributed to decreasing death rates, there is still a large cohort of patients who do not respond to such strategies. A major proportion of cancer-related deaths is caused due to metastasis instead of the primary tumor, and hence stopping any event out of adhesion, communication, and migration of tumor cells serves as a possible treatment for cancer [ 2 ]. Though insights into the invasion and migration of tumor cells have been gained, there is a need to understand the genomic basis of these processes, especially the role of glycosylation in metastasis [ 3 ].…”