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A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells
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A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells
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A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells
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Journal Article
A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells
2021
Overview
Elevated aldehyde dehydrogenase (ALDH) activity correlates with poor outcome for many solid tumors as ALDHs may regulate cell proliferation and chemoresistance of cancer stem cells (CSCs). Accordingly, potent, and selective inhibitors of key ALDH enzymes may represent a novel CSC-directed treatment paradigm for ALDH+ cancer types. Of the many ALDH isoforms, we and others have implicated the elevated expression of ALDH1A3 in mesenchymal glioma stem cells (MES GSCs) as a target for the development of novel therapeutics. To this end, our structure of human ALDH1A3 combined with in silico modeling identifies a selective, active-site inhibitor of ALDH1A3. The lead compound, MCI-INI-3, is a selective competitive inhibitor of human ALDH1A3 and shows poor inhibitory effect on the structurally related isoform ALDH1A1. Mass spectrometry-based cellular thermal shift analysis reveals that ALDH1A3 is the primary binding protein for MCI-INI-3 in MES GSC lysates. The inhibitory effect of MCI-INI-3 on retinoic acid biosynthesis is comparable with that of ALDH1A3 knockout, suggesting that effective inhibition of ALDH1A3 is achieved with MCI-INI-3. Further development is warranted to characterize the role of ALDH1A3 and retinoic acid biosynthesis in glioma stem cell growth and differentiation.Using in silico modeling, Li et al. identify a selective inhibitor for aldehyde dehydrogenase isoform ALDH1A3, which is highly expressed in mesenchymal glioma stem cells and therefore a potential drug target. They solve the structure of the ALDH1A3/MCI-INI-3 inhibitor complex and find that the inhibitor is as efficient as ALDH1A3 depletion in preventing retinoic acid biosynthesis.
