Strategies to reduce late-stage drug attrition due to mitochondrial toxicity

Area of Science:

• Biochemistry
• Pharmacology
• Toxicology

Background:

• Mitochondrial dysfunction is a significant factor in drug-induced toxicities.
• Early identification of mitochondrial liabilities is critical to prevent late-stage drug development failures.
• Traditional methods for assessing mitochondrial dysfunction are often inadequate for routine screening.

Purpose of the Study:

• To develop and implement a high-throughput screening method for assessing mitochondrial liabilities.
• To identify drug candidates with potential mitochondrial toxicity early in the development process.

Main Methods:

• A novel high-throughput screen was developed to measure oxygen consumption.
• Oxygen consumption is a key indicator of mitochondrial status and function.

Main Results:

• The screen successfully identified mitochondrial liabilities in certain drug classes.
• A dichotomy was observed, with some drugs within major classes showing liabilities while others did not.
• This suggests that mitochondrial toxicity can potentially be separated from drug efficacy.

Conclusions:

• A new, efficient method for assessing mitochondrial dysfunction in drug development has been established.
• The findings support the potential for developing safer drugs by mitigating mitochondrial liabilities.
• Future drug development can benefit from early identification and management of mitochondrial risks.