2. Academic Validation
  3. A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells

A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells

  • Commun Biol. 2021 Dec 21;4(1):1420. doi: 10.1038/s42003-021-02949-7.
Jianfeng Li 1 2,  Silvia Garavaglia 3,  Zhaofeng Ye 4 5,  Andrea Moretti 3 6,  Olga V Belyaeva 7,  Alison Beiser 1 2,  Md Ibrahim 1 2,  Anna Wilk 1 2,  Steve McClellan 1,  Alla V Klyuyeva 7,  Kelli R Goggans 7,  Natalia Y Kedishvili 7,  E Alan Salter 8,  Andrzej Wierzbicki 8,  Marie E Migaud 1 2,  Steven J Mullett 9,  Nathan A Yates 9,  Carlos J Camacho 4,  Menico Rizzi 10,  Robert W Sobol 11 12
Affiliations

Affiliations

  • 1 Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA.
  • 2 Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, AL, 36604, USA.
  • 3 Department of Pharmaceutical Sciences, University of Piemonte Orientale, Largo Donegani 2, 28100, Novara, Italy.
  • 4 Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
  • 5 School of Medicine, Tsinghua University, Beijing, China.
  • 6 Structural Plant Biology Laboratory, Department of Botany and Plant Biology, University of Geneva, 1211, Geneva, Switzerland.
  • 7 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Schools of Medicine and Dentistry, 720 20th Street South, Kaul 440B, Birmingham, AL, 35294, USA.
  • 8 Department of Chemistry, University of South Alabama, 6040 USA South Drive, Mobile, AL, 36688, USA.
  • 9 Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
  • 10 Department of Pharmaceutical Sciences, University of Piemonte Orientale, Largo Donegani 2, 28100, Novara, Italy. menico.rizzi@uniupo.it.
  • 11 Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA. rwsobol@southalabama.edu.
  • 12 Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, AL, 36604, USA. rwsobol@southalabama.edu.
PMID: 34934174 DOI: 10.1038/s42003-021-02949-7
Abstract

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.

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