Recently, the role of human aldehyde dehydrogenase (ALDH) isoenzymes has been a subject of interest as they play key roles in both healthy and disease conditions. The human ALDH superfamily consists of 19 isoenzymes that are responsible for the metabolism of aldehydes. The ALDH1A subfamily, in particular, metabolizes retinaldehyde and is involved in the regulation of important processes including cell differentiation, proliferation and cell death. ALDH1A isoenzymes have been implicated as key contributors to cancer outcomes. ALDH1A activity is used as a marker for cancer stem cells. In accordance with this, high ALDH1A activity correlates with reduced survival, increased chemo-resistance and increased chance of relapse in several solid cancer types, including breast and ovarian. Despite the clear importance of ALDH1A enzymes in cancer, the exact roles of these enzymes are unclear. ALDH1A subfamily inhibitors may help uncover the contributions of individual isoenzymes in healthy and disease conditions. This study focused on developing structure-activity relationships for ALDH1A inhibitors, based on our initial hit compound, CM10, using enzyme kinetics assays, structural biology and cell culture experiments. We performed an initial screening assay against the 1A isoenzymes and followed it up with EC<sub>50</sub> determination. The screening results showed that the CM10 analogs inhibited effectively ALDH1A activity. These findings are consistent with prior survey of compounds from this same chemical series and extend the findings into novel chemical entities. The development of these ALDH1A inhibitors are leads toward potential treatments that could improve of patient outcomes for solid tumors that develop resistance to standard therapies.

Characterization of aldehyde dehydrogenase 1A (ALDH1A) inhibitors for cancer treatment

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.