Targeting ALDH7A1 with covalent inhibitors reveals new chemical space for prostate cancer therapy

Area of Science:

• Oncology
• Medicinal Chemistry
• Biochemistry

Background:

• Prostate cancer (PCa) poses a significant global health challenge.
• Therapy resistance leads to metastatic castration-resistant prostate cancer with limited treatment avenues.
• Aldehyde dehydrogenase 7A1 (ALDH7A1) is an emerging oncogenic driver in PCa, yet selective inhibitors are unavailable.

Purpose of the Study:

• To identify and characterize novel, selective inhibitors of ALDH7A1.
• To explore the therapeutic potential of ALDH7A1 inhibition in prostate cancer models.

Main Methods:

• Screening of 3-bromo-4,5-dihydroisoxazole derivatives to identify ALDH7A1 inhibitors.
• Assessing compound selectivity against ALDH4A1 and GAPDH.
• Evaluating compound efficacy on prostate cancer cell lines (DU145, LNCaP) and fibroblasts (Hs27) regarding viability, migration, and cell cycle.
• Measuring intracellular ALDH activity and malondialdehyde levels post-treatment.

Main Results:

• Novel irreversible ALDH7A1 inhibitors targeting Cys330 were identified.
• Compounds 3b and 4b demonstrated potent inhibition of DU145 cell viability (low μM IC50), migration, and cell cycle progression.
• Selective inhibition of ALDH7A1 was confirmed with minimal effects on ALDH4A1 and GAPDH.
• Inhibition of ALDH activity and increased oxidative stress (malondialdehyde accumulation) were observed in treated DU145 cells.

Conclusions:

• ALDH7A1 is validated as a druggable target for prostate cancer therapy.
• The identified 3-bromo-4,5-dihydroisoxazole derivatives represent a new chemical class for selective covalent ALDH inhibitors.
• These findings offer a promising new strategy for treating advanced prostate cancer.