The BCR-ABL1 fusion gene is the hallmark of the Philadelphia chromosome-positive (Ph+) leukemia, creating a constitutively active ABL1 tyrosine kinase. Current therapy relies on the FDA-approved tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec®), which target the ATP binding site of the BCR-ABL1 kinase. Unfortunately, the acquisition of point mutations in the ATP binding site of the kinase often leads to imatinib resistance
Developing BCR-ABL1 inhibitors with a different inhibition modality that do not target the ATP binding site will solve the imatinib resistance conditions.

UNMET NEED
There are no effective treatments in haematological cancer that express BCR-ABL1 mutants that are not sensitive to the first-line treatment using the drug imatinib. Indeed, new imatinib derivatives were developed, but they do not provide complete solutions, being either ineffective (e.g., for treating the BCR-ABL1- T315I mutant) or toxic.

OUR SOLUTION
Our approach is to develop ‘substrate competitive’ inhibitors (SCIs) that exert their inhibitory action by binding to the substrate-binding site of the BCR-ABL1 kinase. 
We propose that such inhibitors will be effective under imatinib resistance conditions. Our strategy is to develop SCI peptides for ABL1 that will serve as templates for pharmacophore design

OUR ADVANTAGE AND PROGRESS
Using a unique computational approach, we designed and synthesized short SCI peptides for ABL1. The SCI peptides inhibited both wild-type and the drug therapy-resistant missense mutants (ABL1-T315I, and- E255K) with IC50 ~ 1µM. The leading SCI peptide E6 was an effective inhibitor in imatinib-sensitive or resistant leukemia cells.