Deubiquitinating ALDH1A3 key to maintaining the culprit of aggressive brain cancer

Wakimoto, Hiroaki

doi:10.1172/jci128742

Cited by 1 publication

(1 citation statement)

References 25 publications

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“…ALDH1A3 interacts with autophagy adaptor protein p62 or ubiquitin‐specific protease 9X, resulting in induced polyubiquitination or deubiquitination of ALDH1A3. The regulation of ALDH1A3 level through ubiquitin‐proteasome system affects the activation of cancer stem cells (Poturnajova et al, 2021; Wakimoto, 2019). However, known roles of ALDH1A3 protein, such as retinoic acid biosynthesis, and its relationship with cancer and its mode of action have not been entirely clarified.…”

Section: Resultsmentioning

confidence: 99%

Identification of a novel ALDH1A3‐selective inhibitor by a chemical probe with unrelated bioactivity: An approach to affinity‐based drug target discovery

et al. 2022

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The identification of biologically active target compounds and their binding proteins is important in mechanism-of-action studies for drug development.Additionally, the newly discovered binding proteins provide unforeseen ideas for novel drug discovery and for subsequent structural transformation to improve target specificity. Based on the lead and final candidate compounds related to the type 5 phosphodiesterase (PDE5) inhibitor E4021, we designed chemical probes and identified their target proteins by the affinity chromatography approach.Aldehyde dehydrogenase family 1 member A3 (ALDH1A3), currently reported as a cancer stem cell target, was clearly isolated as a binding protein of the lead 'immature' inhibitor probe against PDE5. In the early derivatization to the closely related structure, Compound 5 (ER-001135935) was found to significantly inhibit ALDH1A3 activity. The discovery process of a novel ALDH1A3-selective inhibitor with affinity-based binder identification is described, and the impact of this identification method on novel drug discovery is discussed.

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Section: Resultsmentioning

confidence: 99%