A Selective Competitive Inhibitor Of Aldehyde Dehydrogenase 1a3 Hinders Cancer Cell Growth, Invasiveness And Stemness In Vitro

Simple SummaryThe aldehyde dehydrogenases enzymes (ALDHs) are promising drug targets in cancer therapy. ALDHs are members of an enzymatic superfamily composed by 19 isoforms involved in the oxidation of aldehydes, with a scavenger role. Among them, the isoform ALDH1A3 is a cancer biomarker since it is highly expressed in cancer stem cells characterized by a marked drug resistance and the capacity to promote self-renewal, clonogenic growth and tumour-initiating capacity. In this paper, we present the first highly potent and selective ALDH1A3 inhibitor able to induce cytotoxic effects and to reduce cell migration and stemness of ALDH1A3-positive cancer cells. We propose the targeting of the ALDH1A3 enzyme as a promising approach for improving the treatments outcomes of patients affected by ALDH1A3-positive cancers.Aldehyde dehydrogenase 1A3 (ALDH1A3) belongs to an enzymatic superfamily composed by 19 different isoforms, with a scavenger role, involved in the oxidation of a plethora of aldehydes to the respective carboxylic acids, through a NAD+-dependent reaction. Previous clinical studies highlighted the high expression of ALDH1A3 in cancer stem cells (CSCs) correlated to a higher risk of cancer relapses, chemoresistance and a poor clinical outcome. We report on the structural, biochemical, and cellular characterization of NR6, a new selective ALDH1A3 inhibitor derived from an already published ALDH non-selective inhibitor with cytotoxic activity on glioblastoma and colorectal cancer cells. Crystal structure, through X-Ray analysis, showed that NR6 binds a non-conserved tyrosine residue of ALDH1A3 which drives the selectivity towards this isoform, as supported by computational binding simulations. Moreover, NR6 shows anti-metastatic activity in wound healing and invasion assays and induces the downregulation of cancer stem cell markers. Overall, our work confirms the role of ALDH1A3 as an important target in glioblastoma and colorectal cells and propose NR6 as a promising molecule for future preclinical studies.