Design of substrate-based BCR-ABL kinase inhibitors using the cyclotide scaffold

Huang, Yen-Hua, Henriques, Sonia T., Wang, Conan K., Thorstholm, Louise, Daly, Norelle L., Kaas, Quentin and Craik, David J. (2015) Design of substrate-based BCR-ABL kinase inhibitors using the cyclotide scaffold. Scientific Reports, 5 1-15. doi:10.1038/srep12974


Author Huang, Yen-Hua
Henriques, Sonia T.
Wang, Conan K.
Thorstholm, Louise
Daly, Norelle L.
Kaas, Quentin
Craik, David J.
Title Design of substrate-based BCR-ABL kinase inhibitors using the cyclotide scaffold
Journal name Scientific Reports   Check publisher's open access policy
ISSN 2045-2322
Publication date 2015-08-12
Sub-type Article (original research)
DOI 10.1038/srep12974
Open Access Status DOI
Volume 5
Start page 1
End page 15
Total pages 15
Publisher Nature Publishing Group
Collection year 2016
Language eng
Formatted 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.
Keyword Cyclotide scaffold
BCR-ABL kinase inhibitors
Chronic myeloid leukemia (CML)
CML treatments
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
 
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