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Published on: March 31, 2023
STA-55, an Easily Accessible, Broad-Spectrum, Activity-Based Aldehyde Dehydrogenase Probe
Sebastiaan T A Koenders1, Eva J van Rooden1, Hans van den Elst2
1Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
Abstract:
Aldehyde dehydrogenases (ALDHs) convert aldehydes into carboxylic acids and are often upregulated in cancer. They have been linked to therapy resistance and are therefore potential therapeutic targets. However, only a few selective and potent inhibitors are currently available for this group of enzymes. Competitive activity-based protein profiling (ABPP) would aid the development and validation of new selective inhibitors. Herein, a broad-spectrum activity-based probe that reports on several ALDHs is presented. This probe was used in a competitive ABPP protocol against three ALDH inhibitors in lung cancer cells to determine their selectivity profiles and establish their target engagement.
Insights
Aldehyde dehydrogenases (ALDHs) are upregulated in cancer and linked to therapy resistance. A new probe helps profile ALDH inhibitors, aiding the development of targeted cancer therapies.
Area of Science:
- Biochemistry
- Enzymology
- Cancer Biology
Background:
- Aldehyde dehydrogenases (ALDHs) are enzymes crucial for aldehyde metabolism.
- ALDHs are frequently upregulated in various cancers.
- Their role in cancer progression and therapy resistance highlights their potential as therapeutic targets.
Purpose of the Study:
- To develop and utilize a novel activity-based probe (ABP) for broad-spectrum ALDH profiling.
- To assess the selectivity of existing ALDH inhibitors using competitive activity-based protein profiling (ABPP).
- To validate target engagement of ALDH inhibitors in a relevant cancer model.
Main Methods:
- Synthesis of a broad-spectrum activity-based probe for ALDHs.
- Application of competitive ABPP using the developed probe.
- Analysis of ALDH inhibitor selectivity profiles in lung cancer cells.
Main Results:
- A novel ABP capable of reporting on multiple ALDH enzymes was successfully developed.
- Competitive ABPP revealed distinct selectivity profiles for three tested ALDH inhibitors.
- The study established target engagement for these inhibitors in lung cancer cells.
Conclusions:
- The developed ABP is a valuable tool for evaluating ALDH inhibitors.
- Understanding inhibitor selectivity is critical for developing effective cancer therapies targeting ALDHs.
- This approach facilitates the discovery and validation of new ALDH-targeted drugs.
