Design of substrate-based BCR-ABL kinase inhibitors using the cyclotide scaffold
Huang, Yen-hua, Henriques, Sónia 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. 12974.
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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.
| Item ID: | 44444 |
|---|---|
| Item Type: | Article (Research - C1) |
| ISSN: | 2045-2322 |
| Additional Information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Funders: | National Health and Medical Research Council of Australia (NHMRC)., Discovery Early Career Research Award (DECRA) |
| Projects and Grants: | NHMRC APP1060225, NHMRC APP1026501, DECRA DE12010315, NHMRC 536578 |
| Date Deposited: | 17 Jun 2016 02:21 |
| FoR Codes: | 11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics) @ 50% 11 MEDICAL AND HEALTH SCIENCES > 1112 Oncology and Carcinogenesis > 111201 Cancer Cell Biology @ 50% |
| SEO Codes: | 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920101 Blood Disorders @ 50% 97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 50% |
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