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.
Highlights
Chronic myeloid leukemia (CML) is a hematopoietic disease characterized by increased and unregulated growth of predominantly myeloid cells
Clinical resistance to tyrosine kinase inhibitors (TKIs) therapy is a significant issue in the treatment of chronic myeloid leukemia (CML) patients in the advanced stage of the disease[1,6], primarily because the induction of point mutations in the breakpoint cluster (BCR)-ABL kinase domain impair the interaction between IM and the ATP binding cleft[7]
This model was built by homology with the crystal structures of an abltide variant bound to an inactive form of Abl kinase[5] and of an active form of protein kinase A bound to a peptide substrate, ATP and two magnesium ions (PDB ID: 1atp)
Summary
Chronic myeloid leukemia (CML) is a hematopoietic disease characterized by increased and unregulated growth of predominantly myeloid cells. Philadelphia chromosome (Ph), the cytogenetic hallmark of CML, results from the reciprocal translocation of chromosomes 9 and 22 This fusion between breakpoint cluster (BCR) gene from chromosome 22 and Abelson (ABL) tyrosine kinase gene from chromosome 91,2 forms the BCR-ABL oncogene. Philadelphia chromosome-positive (Ph+) patients in chronic phase of CML rely on sustained administration of small-molecule tyrosine kinase inhibitors (TKIs). Clinical resistance to TKI therapy is a significant issue in the treatment of CML patients in the advanced stage of the disease[1,6], primarily because the induction of point mutations in the BCR-ABL kinase domain impair the interaction between IM and the ATP binding cleft[7].
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