Safety assessment considerations and strategies for targeted small molecule cancer therapeutics in drug discovery

Area of Science:

• Oncology
• Pharmacology
• Drug Discovery

Background:

• Most experimental drugs fail clinical trials, with oncology therapeutics having a particularly low approval rate (5%).
• Clinical safety and efficacy are primary reasons for the failure of oncologic drugs in development.
• Drug development failures incur significant financial losses for pharmaceutical companies.

Purpose of the Study:

• To present concepts and strategies for reducing the attrition of small molecule oncology therapeutic drug candidates.
• To highlight the importance of early-stage drug discovery efforts in mitigating late-stage failures.
• To address toxicity as a key factor in drug candidate attrition.

Main Methods:

• Reviewing current strategies in drug development and discovery for reducing attrition.
• Identifying key areas in drug discovery for enhanced focus: target validation, compound selectivity, and toxicity mitigation.
• Discussing the benefits of lead compound optimization in reducing drug candidate failure.

Main Results:

• Early-stage drug discovery efforts, specifically target validation and compound selectivity analysis, offer greater benefits than later-stage development strategies for reducing attrition.
• Investigating ancillary methods to mitigate toxicity, particularly target-related effects, is crucial.
• While lead compound optimization is recognized, its application varies, suggesting room for improvement.

Conclusions:

• Implementing robust strategies in early drug discovery can significantly decrease the failure rate of small molecule oncology therapeutics.
• A balanced approach to compound selectivity, considering both efficacy and toxicity, is essential.
• Proactive investigation and mitigation of toxicity are critical for successful drug development in oncology.