Deconvoluting Kinase Inhibitor Induced Cardiotoxicity.

Area of Science:

• Biochemistry and Pharmacology
• Cardiovascular Biology
• Drug Discovery

Background:

• Kinase inhibitors (KIs) often cause cardiotoxicity, limiting their clinical use.
• Identifying specific kinases responsible for KI-induced cardiotoxicity is complex due to polypharmacology.
• Understanding these causative kinases is crucial for developing safer KI therapeutics.

Purpose of the Study:

• To identify kinases that modulate cardiomyocyte beating and contribute to cardiotoxicity.
• To develop a predictive model for functional cardiotoxicity of kinase inhibitors.
• To advance the design of safer kinase inhibitor medicines.

Main Methods:

• Assessed effects of 65 KIs on human iPSC-CM beating using label-free impedance.
• Correlated kinase inhibition profiles with CM beat changes via computational analysis.
• Validated identified kinases through gene knockdown and assessed a predictive model against clinical data.

Main Results:

• Identified 30 kinases correlated with CM beat changes and expressed in cardiac tissue.
• Discovered kinases regulating excitation-contraction cascade, including calcium flux and action potential duration.
• Developed a predictive model using three sentinel kinases (RPS6KB1, FAK, STK35) with high accuracy in vitro and clinical translation.

Conclusions:

• This work identifies key kinases influencing cardiomyocyte function and cardiotoxicity.
• A novel predictive model for KI cardiotoxicity offers a pathway to safer drug design.
• Findings stimulate further investigation into underappreciated cardiovascular signaling pathways involving kinases.