Development of retinoid nuclear receptor pathway antagonists through targeting aldehyde dehydrogenase 1A3

Area of Science:

• Biochemistry
• Immunology
• Oncology

Background:

• Aldehyde dehydrogenase 1a3 (ALDH1A3) is implicated in cardiometabolic diseases and cancer.
• Its precise role in disease progression and the lack of effective inhibitors remain significant challenges.
• The canonical function of ALDH1A enzymes in converting retinaldehyde to all-trans retinoic acid (atRA) is paradoxically linked to tumor suppression.

Purpose of the Study:

• To elucidate the paradoxical role of ALDH1A3 in cancer.
• To investigate the mechanism by which ALDH1A3 promotes tumorigenesis.
• To identify and develop novel therapeutic inhibitors of ALDH1A3.

Main Methods:

• Utilized a hybrid in silico and high-throughput screening approach.
• Performed medicinal optimization of identified compounds.
• Assessed anti-tumor immunotherapeutic activity of ALDH1A3 antagonists.

Main Results:

• ALDH1A3 is overexpressed in various cancers, with tumor cells exhibiting reduced sensitivity to retinoid signaling.
• ALDH1A3-derived atRA acts in a paracrine manner to suppress anti-tumor immunity by activating retinoid signaling in immune cells.
• Identified first-in-class, oral, and safe ALDH1A3 antagonists with potent anti-tumor immunotherapeutic activity.

Conclusions:

• ALDH1A3 promotes cancer progression through paracrine suppression of anti-tumor immunity, resolving the paradox of its role in cancer.
• Developed novel ALDH1A3 antagonists represent a promising new class of immunotherapeutics for cancer treatment.
• The identified inhibitors possess an optimized drug development profile for clinical translation.