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Case Study 1 

Reengineering an Antiarrhythmic Drug for Improved Potency & Safety

This case study explored reengineering of Mexiletine using the ValaDATE.AI™ platform to enhance its potency and safety. Mexiletine treats life-threatening ventricular arrhythmias and long QT syndrome, but it can cause side effects like irregular heartbeats and liver issues.

hiPSC Cell Generation

Human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes were generated from patients with long QT syndrome type 3 (LQT3) and healthy donors.

Screening Strategy​

130 Mexiletine analogues were screened to identify compounds that shorten the action potential duration (APD) without causing proarrhythmic effects.

Functional Evaluation​

The ValaDATE.AI™ platform was utilized to analyze APD shortening, potency, and efficacy, resulting in the identification of 17 promising analogues.

Lead Candidates​

This study identified 4 lead candidates that showed improved therapeutic potential and reduced toxicity compared to Mexiletine.

McKeithan et al. Cell Stem Cell 2020

Case Study 2

Decrease the Cardiotoxicity Liability of an Oncology Drug

This case study utilized ValaDATE.AI™ to reduce the cardiotoxicity of Ponatinib, an oncology drug for Chronic Myelogenous Leukemia (CML) patients harboring the BCR-ABL T315I mutation. Although Ponatinib is effective, it can cause life-threatening cardiac side effects in some patients.  

Chemical Diversification/Synthesis

Approximately 150 compounds were synthesized and evaluated to find a less cardiotoxic alternative to Ponatinib.

Functional Evaluation​

The ValaDATE.AI™ platform was employed to identify compounds with high tumor inhibition and minimal cardiotoxicity.  

Lead Candidates​

Analogues 33a and 36a emerged as promising candidates, demonstrating tumor inhibition comparable to Ponatinib, while significantly reducing cardiotoxicity.

Anti-Cancer & Cardiotoxicity Assays

Compounds were tested for their ability to inhibit tumor growth and induce cardiotoxicity using a range of assays, including:

  • Cell Proliferation: Tested on CML cells (both wild-type and T315I mutant BCR-ABL).
  • Vasculogenesis: Assessed using human cardiac microvascular endothelial cells.
  • Contractility:  Evaluated using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).

Hnatiuk et al. Cancer Research 2022