STA-55, an Easily Accessible, Broad-Spectrum, Activity-Based Aldehyde Dehydrogenase Probe

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.