Overcoming Challenges of PROTAC Bioanalysis to Unleash the Potential

As a novel strategy for new drug research and development, Proteolysis-Targeting Chimera (PROTAC)* technology has continuously evolved and undergone numerous updates. Despite PROTAC have substantial potential, their complex structures may result in poor druggability, posing huge challenges to clinical trials, bioanalysis, and PK/PD studies.

What are the critical factors for the success of PROTAC bioanalysis?

1. Optimal MS parameters: PROTAC are prone to in-source fragmentation, which could be reduced by optimizing the low ionizing energy and ion source temperature and seeking multiple charges to improve sensitivity.

2. Peak shape optimization- peak splitting: It is necessary to optimize the peak shape by adjusting the liquid chromatography method to achieve smoother analysis.

3. Elimination of non-specific binding: The exposed ions may also non-specifically bind to experiment material such as glass or plastic ¹. Hence, it is essential to eliminate non-specific adsorption to prevent compound loss during the operation.

4. Controllable substrate stability: Some PROTAC become highly unstable in the frozen matrix, and no inhibitors have been identified to effectively stabilize them. Therefore, a fresh blank matrix should be used to prepare calibration standards and quality control samples.

How to conduct the PROTAC bioanalysis

Based on the different characteristics of PROTAC and the above-mentioned analysis experience, the PROTAC bioanalysis process includes (1) Optimization of MS parameters, (2) Optimization of liquid chromatography conditions, (3) Elimination of non-specific binding, (4) Optimization of the sample processing procedure, and (5) Method reproducibility.

Looking ahead：

In the realm of PROTAC development, the PROTAC compound analysis strategy developed by the Non-GLP Bioanalysis team of the DMPK Services Department of WuXi AppTec plays a vital role in supporting customers to efficiently conduct experiments with accurate and reliable data, facilitating their drug development process.

To learn more about the strategies for PROTAC Bioanalysis, read the article now.

*PROTAC® is a registered trademark of Arvinas. In this article, PROTAC specifically refers to the abbreviation of Proteolysis-Targeting Chimera as therapeutic modalities.

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