ArticleScientific reports2015
Design of substrate-based BCR-ABL kinase inhibitors using the cyclotide scaffold.
Article in Scientific reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 72 citations in OpenAlex.
- Advances in cyclotide research: bioactivity to cyclotide-based therapeutics.Molecular diversity · 2025Review
- Plant Antimicrobial Oligopeptides with Anticancer Properties as a Source of Biologically Active Peptides-AnInternational journal of molecular sciences · 2025Article
- Recent advances in ASCT2 inhibitors: ligand design and therapeutic applications.Future medicinal chemistry · 2025Review
- A general assay platform to study protein pharmacology using ligand-dependent structural dynamics.Nature communications · 2025Article
- Plant Defense Peptides: Exploring the Structure-Function Correlation for Potential Applications in Drug Design and Therapeutics.ACS omega · 2025Review
- The prospect of substrate-based kinase inhibitors to improve target selectivity and overcome drug resistance.Chemical science · 2024Review
- Discovery and Characterization of MaK: A Novel Knottin Antimicrobial Peptide fromInternational journal of molecular sciences · 2023Article
- On chip microfluidic separation of cyclotides.Turkish journal of chemistry · 2023Article
- Using the Cyclotide Scaffold for Targeting Biomolecular Interactions in Drug Development.Molecules (Basel, Switzerland) · 2022Review
- Verbascoside potentiates the effect of tyrosine kinase inhibitors on the induction of apoptosis and oxidative stress via the Abl-mediated MAPK signalling pathway in chronic myeloid leukaemia.Experimental and therapeutic medicine · 2022Article
- Comparison of a Short Linear Antimicrobial Peptide with Its Disulfide-Cyclized and Cyclotide-Grafted Variants against Clinically Relevant Pathogens.Microorganisms · 2021Article
- Methodologies for Backbone Macrocyclic Peptide Synthesis Compatible With Screening Technologies.Frontiers in chemistry · 2020Review
- General lack of structural characterization of chemically synthesized long peptides.Protein science : a publication of the Protein Society · 2019Review
- The Potential of the Cyclotide Scaffold for Drug Development.Biomedicines · 2019Review
- Using backbone-cyclized Cys-rich polypeptides as molecular scaffolds to target protein-protein interactions.The Biochemical journal · 2019Review
- Designing macrocyclic disulfide-rich peptides for biotechnological applications.Nature chemical biology · 2018Article
- Anthelmintic niclosamide suppresses transcription of BCR-ABL fusion oncogene via disabling Sp1 and induces apoptosis in imatinib-resistant CML cells harboring T315I mutant.Cell death & disease · 2018Article
- Cyclotides, a versatile ultrastable micro-protein scaffold for biotechnological applications.Bioorganic & medicinal chemistry letters · 2017Review
- Cyclotides: Overview and Biotechnological Applications.Chembiochem : a European journal of chemical biology · 2017Review
- Targeting kinase signaling pathways with constrained peptide scaffolds.Pharmacology & therapeutics · 2017Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The constitutively active tyrosine kinase BCR-ABL is the underlying cause of chronic myeloid leukemia (CML). Current CML treatments rely on the long-term use of tyrosine kinase inhibitors (TKIs), which target the ATP binding site of BCR-ABL. Over the course of treatment, 20-30% of CML patients develop TKI resistance, which is commonly attributed to point mutations in the drug-binding region. We design a new class of peptide inhibitors that target the substrate-binding site of BCR-ABL by grafting sequences derived from abltide, the optimal substrate of Abl kinase, onto a cell-penetrating cyclotide MCoTI-II. Three grafted cyclotides show significant Abl kinase inhibition in vitro in the low micromolar range using a novel kinase inhibition assay. Our work also demonstrates that a reengineered MCoTI-II with abltide sequences grafted in both loop 1 and 6 inhibits the activity of [T315I]Abl in vitro, a mutant Abl kinase harboring the "gatekeeper" mutation which is notorious for being multidrug resistant. Results from serum stability and cell internalization studies confirm that the MCoTI-II scaffold provides enzymatic stability and cell-penetrating properties to the lead molecules. Taken together, our study highlights that reengineered cyclotides incorporating abltide-derived sequences are promising substrate-competitive inhibitors for Abl kinase and the T315I mutant.
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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.