ALDH (aldehyde dehydrogenase family, including ALDH1A1/ALDH3A1)

Class

Small molecule enzyme inhibitor

Pathway

Aldehyde detoxification / chemoresistance and leukemic stem cell metabolism

Aldehyde dehydrogenases (ALDH) are a family of enzymes that oxidize reactive aldehydes—byproducts of normal metabolism and of certain drugs—into less toxic carboxylic acids. Isoforms such as ALDH1A1 and ALDH3A1 are broadly expressed but become particularly important in the context of cancer, where elevated ALDH activity is a marker of stem-like tumor cells, including leukemic stem cells, and contributes to their survival and to resistance against chemotherapy agents that work by generating toxic aldehyde intermediates (notably cyclophosphamide-class drugs). By detoxifying these reactive species, ALDH-high cells can survive treatments that would otherwise kill more differentiated tumor cells, allowing relapse from a residual stem-like population. Inhibiting ALDH activity is therefore explored as a strategy to sensitize resistant or stem-like tumor cells to chemotherapy and to directly impair the metabolic state that supports their persistence. Because ALDH enzymes also participate in normal physiology, including retinoic acid signaling and alcohol metabolism, selectivity among family members is a relevant consideration in drug design. This mechanism is studied primarily in hematologic malignancies such as acute myeloid leukemia, where leukemic stem cells are thought to rely on ALDH-mediated detoxification, as well as in solid tumors with chemoresistant, stem-like subpopulations.