Small-molecule inhibitors of tankyrases as prospective therapeutics for cancer
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(Published version)
Date
2022
Authors
Yu, M.
Yang, Y.
Sykes, M.
Wang, S.
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Journal article
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Journal of Medicinal Chemistry, 2022; 65(7):5244-5273
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Abstract
Tankyrases are multifunctional poly(adenosine diphosphate-ribose) polymerases that regulate diverse biological processes including telomere maintenance and cellular signaling. These processes are often implicated in a number of human diseases, with cancer being the most prevalent example. Accordingly, tankyrase inhibitors have gained increasing attention as potential therapeutics. Since the discovery of XAV939 and IWR-1 as the first tankyrase inhibitors over two decades ago, tankyrase-targeted drug discovery has made significant progress. This review starts with an introduction of tankyrases, with emphasis placed on their cancer-related functions.
Small-molecule inhibitors of tankyrases are subsequently delineated based on their distinct modes of binding to the enzymes. In addition to inhibitors that compete with oxidized nicotinamide adenine dinucleotide (NAD+) for binding to the catalytic domain of tankyrases, non-NAD+-competitive inhibitors are detailed. This is followed by a description of three clinically trialled tankyrase inhibitors. To conclude, some of challenges and prospects in developing tankyrase-targeted cancer therapies are discussed.
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Data source: Supporting information, https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c02139
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Copyright 2021 American Chemical Society
Access Condition Notes: Accepted manuscript available after 1 April 2023