Development of novel ALDH1A3 inhibitors potentially useful in the treatment of cancer

The World Health Organization identifies breast cancer as the most prevalent cancer, affecting 7.8 million individuals from 2015 to 2020. Mortality often stems from metastatic disease recurrence and drug resistance, particularly due to Cancer Stem Cells (CSCs), which drive tumor initiation and progression. Aldehyde Dehydrogenase 1A3 (ALDH1A3) is a marker for breast CSCs correlated to a higher risk of cancer relapses, chemoresistance, and poor clinical outcomes. While ALDH1A3, a member of the ALDH superfamily (EC: 1.2.1.5), emerged as a valuable target, developing potent and selective inhibitors remains challenging. Recent optimization efforts yielded VE3 (patent application filed in Italy), a promising anti-ALDH1A3 compound (IC50 of 1.9 nM by Aldefluor assay), serving as a hit compound for developing novel ALDH1A3 inhibitors with an imidazo[1,2-a]pyridine core. Building on the established host-home institution collaboration, this project aims to provide potent and selective ALDH1A3 inhibitors as derivatives of VE3 for future application in breast cancer treatment. It will evaluate their functional profiles, selectively inhibiting ALDH1A isoforms and their antiproliferative activity in MDA-MB-231 cells overexpressing ALDH1A3 or ALDH1A1. Ultimately, identifying a potent ALDH1A3 inhibitor will be a step forward toward transferring the ALDH1A3-targeting strategy into clinical practice, gaining a better understanding of ALDH1A3’s molecular mechanisms.

Faculty Supervisor:

Paola Marcato

Student:

Partner:

University of Pisa

Discipline:

Life Sciences

Sector:

Education

University:

Dalhousie University

Program: