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

Area of Science:

• Oncology
• Pharmacology
• Medicinal Chemistry

Background:

• Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL are crucial for treating chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL).
• Existing TKIs face challenges due to drug resistance, particularly the T315I mutation, and significant cardiotoxicity.
• Ponatinib is effective against resistant mutations but exhibits high cardiotoxicity.

Purpose of the Study:

• To design and synthesize novel, potent BCR-ABL inhibitors targeting the T315I mutation.
• To identify inhibitors with improved safety profiles, specifically reduced cardiotoxicity.
• To evaluate the efficacy of new compounds against both wild-type and mutant BCR-ABL kinase.

Main Methods:

• Structure-guided drug design approach.
• Synthesis and systematic structure-activity relationship (SAR) studies of novel inhibitor series.
• Utilized induced pluripotent stem cell (iPSC)-derived cardiomyocyte models to assess cardiotoxicity.
• Assayed kinase inhibition activity against native BCR-ABL and T315I mutant forms.

Main Results:

• Identified two novel compounds, 33a and 36a, demonstrating potent inhibition of both native BCR-ABL and the T315I mutant.
• These compounds represent the most cardiac-safe TKIs reported to date.
• The identified inhibitors show significant potential for treating CML patients with the T315I mutation.

Conclusions:

• Novel BCR-ABL inhibitors, 33a and 36a, have been successfully designed and validated.
• These compounds offer a promising therapeutic strategy for CML and ALL patients with T315I mutations, addressing both efficacy and safety concerns.
• The developed inhibitors exhibit a favorable safety profile, particularly regarding cardiotoxicity, marking a significant advancement in TKI development.