Reengineering Ponatinib to Minimize Cardiovascular Toxicity.

Area of Science:

• Oncology
• Cardiovascular Pharmacology
• Medicinal Chemistry

Background:

• Small molecule tyrosine kinase inhibitors (TKIs) have advanced cancer therapy but often cause severe cardiotoxicity.
• Ponatinib, a potent TKI for BCR-ABL-mutated chronic myeloid leukemia (CML), exhibits significant cardiotoxicity, limiting its use.
• Identifying and mitigating TKI-induced cardiotoxicity is crucial for improving patient outcomes.

Purpose of the Study:

• To engineer safer analogs of ponatinib with reduced cardiotoxicity while maintaining efficacy against T315I-mutated BCR-ABL.
• To investigate the mechanisms underlying ponatinib-induced cardiotoxicity.
• To develop a screening strategy for safer small molecule oncology therapeutics.

Main Methods:

• Parallel screening of cardiovascular toxicity and antitumor efficacy assays.
• In vitro assessment of compound toxicity in human cardiac vasculogenesis and cardiomyocyte contractility models.
• In vivo evaluation of therapeutic window and efficacy in human T315I mutant CML xenograft models.
• Comparative kinase inhibition profiling of ponatinib and its analogs.

Main Results:

• Novel ponatinib analogs demonstrated potent inhibition of T315I BCR-ABL kinase activity and suppressed CML tumor growth.
• The engineered analogs exhibited substantially reduced toxicity in cardiac assays in vitro.
• In vivo studies showed a larger therapeutic window, with analogs causing CML xenograft regression without cardiotoxicity.
• Kinase profiling suggested specific kinases mediate ponatinib's cardiotoxicity.

Conclusions:

• Safer ponatinib analogs have been developed, offering a promising therapeutic option for CML treatment.
• The study highlights an approach using phenotypic assays to reduce cardiotoxicity in small molecule oncology drugs.
• Understanding off-target kinase inhibition is key to designing less cardiotoxic TKIs.