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Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer
Mingfeng Yu1, Yuchao Yang1, Matthew Sykes1
1Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia 5000, Australia.
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.
Insights
Tankyrase inhibitors show promise for treating cancer by targeting key cellular processes. This review details their development, modes of action, and clinical progress for cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Tankyrases are key regulators of telomere maintenance and cellular signaling pathways.
- Dysregulation of tankyrase activity is implicated in various human diseases, particularly cancer.
- Tankyrase inhibitors represent a promising therapeutic strategy for cancer treatment.
Purpose of the Study:
- To review the advancements in tankyrase inhibitor drug discovery.
- To categorize tankyrase inhibitors based on their binding mechanisms.
- To discuss the clinical progress and future prospects of tankyrase-targeted cancer therapies.
Main Methods:
- Literature review of tankyrase inhibitors and their mechanisms.
- Classification of inhibitors based on competition with oxidized nicotinamide adenine dinucleotide (NAD+).
- Summary of clinically trialled tankyrase inhibitors.
Main Results:
- Significant progress has been made since the discovery of early tankyrase inhibitors.
- Inhibitors include those that compete with NAD+ and non-NAD+-competitive agents.
- Three tankyrase inhibitors have advanced to clinical trials.
Conclusions:
- Tankyrase inhibitors offer a targeted approach to cancer therapy.
- Understanding inhibitor binding modes is crucial for drug development.
- Further research and clinical trials are needed to overcome challenges and realize the full potential of tankyrase-targeted therapies.
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