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

Mallesh Pandrala, Arne Antoon N. Bruyneel, Anna P. Hnatiuk, Mark Mercola, Sanjay V. Malhotra

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10898-10919
Number of pages22
JournalJournal of Medicinal Chemistry
Volume65
Issue number16
DOIs
StatePublished - Aug 25 2022

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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