ArticleProceedings of the National Academy of Sciences of the United States of America2018
Iterative optimization yields Mcl-1-targeting stapled peptides with selective cytotoxicity to Mcl-1-dependent cancer cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
45 citing papers in PubMed, 79 citations in OpenAlex.
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- Boosting Drug Discovery: Expanding the Applicability of Fragment Dissolved Molecular Dynamics to Accelerate Binding Mode Elucidation.Journal of chemical information and modeling · 2025Article
- De novo discovery of a molecular glue-like macrocyclic peptide that induces MCL1 homodimerization.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Inhibitory Potential and Binding Thermodynamics of Scyllatoxin-Based BH3 Domain Mimetics Targeting Repressor BCL2 Proteins.Journal of molecular recognition : JMR · 2025Article
- Tackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics.Chemical reviews · 2024Review
- Modeling the Binding of Anticancer Peptides and Mcl-1.International journal of molecular sciences · 2024Article
- Histidine-Covalent Stapled Alpha-Helical Peptides Targeting hMcl-1.Journal of medicinal chemistry · 2024Article
- In silico design of potential Mcl-1 peptide-based inhibitors.Journal of molecular modeling · 2024Article
- β-Sitosterol as a Promising Anticancer Agent for Chemoprevention and Chemotherapy: Mechanisms of Action and Future Prospects.Advances in nutrition (Bethesda, Md.) · 2023Review
- Identification of the Stapled α-Helical Peptide ATSP-7041 as a Substrate and Strong Inhibitor of OATP1B1 In Vitro.Biomolecules · 2023Article
- Stapled Peptides as Direct Inhibitors of Nrf2-sMAF Transcription Factors.Journal of medicinal chemistry · 2023Article
- Rapid Evaluation of Staple Placement in Stabilized α Helices Using Bacterial Surface Display.ACS chemical biology · 2023Article
- Article
- Cytoskeletal regulation of a transcription factor by DNA mimicry via coiled-coil interactions.Nature cell biology · 2022Article
- Harnessing the Therapeutic Potential of Biomacromolecules through Intracellular Delivery of Nucleic Acids, Peptides, and Proteins.Advanced healthcare materials · 2022Review
- Targeting intracellular protein-protein interactions with macrocyclic peptides.Trends in pharmacological sciences · 2022Review
- Discovery, development and application of drugs targeting BCL-2 pro-survival proteins in cancer.Biochemical Society transactions · 2021Review
- The transcription factor reservoir and chromatin landscape in activated plasmacytoid dendritic cells.BMC genomic data · 2021Article
- Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRASActa pharmaceutica Sinica. B · 2021Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Bcl-2 family proteins regulate apoptosis, and aberrant interactions of overexpressed antiapoptotic family members such as Mcl-1 promote cell transformation, cancer survival, and resistance to chemotherapy. Discovering potent and selective Mcl-1 inhibitors that can relieve apoptotic blockades is thus a high priority for cancer research. An attractive strategy for disabling Mcl-1 involves using designer peptides to competitively engage its binding groove, mimicking the structural mechanism of action of native sensitizer BH3-only proteins. We transformed Mcl-1-binding peptides into α-helical, cell-penetrating constructs that are selectively cytotoxic to Mcl-1-dependent cancer cells. Critical to the design of effective inhibitors was our introduction of an all-hydrocarbon cross-link or "staple" that stabilizes α-helical structure, increases target binding affinity, and independently confers binding specificity for Mcl-1 over related Bcl-2 family paralogs. Two crystal structures of complexes at 1.4 Å and 1.9 Å resolution demonstrate how the hydrophobic staple induces an unanticipated structural rearrangement in Mcl-1 upon binding. Systematic sampling of staple location and iterative optimization of peptide sequence in accordance with established design principles provided peptides that target intracellular Mcl-1. This work provides proof of concept for the development of potent, selective, and cell-permeable stapled peptides for therapeutic targeting of Mcl-1 in cancer, applying a design and validation workflow applicable to a host of challenging biomedical targets.
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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.