ArticleJournal of the American Chemical Society2017
Macrocyclized Extended Peptides: Inhibiting the Substrate-Recognition Domain of Tankyrase.
Article in Journal of the American Chemical Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 71 citations in OpenAlex.
- Isatin-based oxime ethers as anticancer agents against human colorectal carcinoma.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Selective Inhibition of CK2: Emerging Strategies and Future Directions.Journal of medicinal chemistry · 2026Review
- Disrupting the tumor-associated TNKS-USP25 protein-protein interface in cancer: structural basis, druggability, and therapeutic opportunities.RSC advances · 2026Review
- Linker Engineering in Stapled Peptides for Enhanced Membrane Permeability: Screening and Optimization Strategies.International journal of molecular sciences · 2026Review
- Tankyrases modulate the hypoxia response through non-catalytic mechanisms affecting HIF-1α.Cell communication and signaling : CCS · 2025Article
- Tackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics.Chemical reviews · 2024Review
- Multiple Molecular Dynamics Simulations and Energy Analysis Unravel the Dynamic Properties and Binding Mechanism of Mutants HIV-1 Protease with DRV and CA-p2.Microbiology spectrum · 2022Article
- Synthesis of medium-ring lactams and macrocyclic peptide mimeticsRSC chemical biology · 2022Article
- Targeting intracellular protein-protein interactions with macrocyclic peptides.Trends in pharmacological sciences · 2022Review
- Macrocyclization strategies for cyclic peptides and peptidomimetics.RSC medicinal chemistry · 2021Review
- Ankyrin repeats in context with human population variation.PLoS computational biology · 2021Article
- Cyclisation strategies for stabilising peptides with irregular conformations.RSC medicinal chemistry · 2021Review
- Tankyrases as modulators of pro-tumoral functions: molecular insights and therapeutic opportunities.Journal of experimental & clinical cancer research : CR · 2021Review
- Engineering mono- and multi-valent inhibitors on a modular scaffold.Chemical science · 2021Article
- Evaluating the Viability of Successive Ring-Expansions Based on Amino Acid and Hydroxyacid Side-Chain Insertion.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
- A FRET-based high-throughput screening platform for the discovery of chemical probes targeting the scaffolding functions of human tankyrases.Scientific reports · 2020Article
- Macrocyclization of an all-d linear α-helical peptide imparts cellular permeability.Chemical science · 2020Article
- Bent Into Shape: Folded Peptides to Mimic Protein Structure and Modulate Protein Function.Peptide science (Hoboken, N.J.) · 2020Article
- Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase.Scientific reports · 2019Article
- Structural and functional analysis of parameters governing tankyrase-1 interaction with telomeric repeat-binding factor 1 and GDP-mannose 4,6-dehydratase.The Journal of biological chemistry · 2019Article
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
We report a double-click macrocyclization approach for the design of constrained peptide inhibitors having non-helical or extended conformations. Our targets are the tankyrase proteins (TNKS), poly(ADP-ribose) polymerases (PARP) that regulate Wnt signaling by targeting Axin for degradation. TNKS are deregulated in many different cancer types, and inhibition of TNKS therefore represents an attractive therapeutic strategy. However, clinical development of TNKS-specific PARP catalytic inhibitors is challenging due to off-target effects and cellular toxicity. We instead targeted the substrate-recognition domain of TNKS, as it is unique among PARP family members. We employed a two-component strategy, allowing peptide and linker to be separately engineered and then assembled in a combinatorial fashion via click chemistry. Using the consensus substrate-peptide sequence as a starting point, we optimized the length and rigidity of the linker and its position along the peptide. Optimization was further guided by high-resolution crystal structures of two of the macrocyclized peptides in complex with TNKS. This approach led to macrocyclized peptides with submicromolar affinities for TNKS and high proteolytic stability that are able to disrupt the interaction between TNKS and Axin substrate and to inhibit Wnt signaling in a dose-dependent manner. The peptides therefore represent a promising starting point for a new class of substrate-competitive inhibitors of TNKS with potential for suppressing Wnt signaling in cancer. Moreover, by demonstrating the application of the double-click macrocyclization approach to non-helical, extended, or irregularly structured peptides, we greatly extend its potential and scope, especially given the frequency with which such motifs mediate protein-protein interactions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.