Designing Novel BCR-ABL Inhibitors for Chronic Myeloid Leukemia with Improved Cardiac Safety

Development of tyrosine kinase inhibitors (TKIs) targeting
the
BCR-ABL oncogene constitutes an effective approach for the treatment
of chronic myeloid leukemia (CML) and/or acute lymphoblastic leukemia.
However, currently available inhibitors are limited by drug resistance
and toxicity. Ponatinib, a third-generation inhibitor, has demonstrated
excellent efficacy against both wild type and mutant BCR-ABL kinase,
including the “gatekeeper” T315I mutation that is resistant
to all other currently available TKIs. However, it is one of the most
cardiotoxic of the FDA-approved TKIs. Herein, we report the structure-guided
design of a novel series of potent BCR-ABL inhibitors, particularly
for the T315I mutation. Our drug design paradigm was coupled to iPSC–cardiomyocyte
models. Systematic structure–activity relationship studies
identified two compounds, 33a and 36a, that
significantly inhibit the kinase activity of both native BCR-ABL and
the T315I mutant. We have identified the most cardiac-safe TKIs reported
to date, and they may be used to effectively treat CML patients with
the T315I mutation.