Design, synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes

  • Bioorg Med Chem. 2018 Dec 1;26(22):5766-5779. doi: 10.1016/j.bmc.2018.10.009.
Angelica R Harper  1 ,  Anh T Le  2 ,  Timothy Mather  3 ,  Anthony Burgett  2 ,  William Berry  1 ,  Jody A Summers  4
Affiliations
  • 1. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States.
  • 2. Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States.
  • 3. Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, United States.
  • 4. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States. Electronic address: [email protected].
PMID: 30409702 DOI: 10.1016/j.bmc.2018.10.009
Abstract

The retinaldehyde dehydrogenase (RALDH) Enzymes, RALDH1, RALDH2, and RALDH3, catalyze the irreversible oxidation of retinaldehyde to all-trans-retinoic acid (ATRA). Despite the importance of the RALDH Enzymes in embryonic development, postnatal growth and differentiation, and in several disease states, there are no commercially available inhibitors that specifically target these isozymes. We report here the development and characterization of a small molecule inhibitor dichloro-all-trans-retinone (DAR) (Summers et al., 2017) that is an irreversible inhibitor of RALDH1, 2, and 3 that effectively inhibits RALDH1, 2, and 3 in the nanomolar range but has no inhibitory activity against mitochondrial ALDH2. These results provide support for the development of DAR as a specific ATRA synthesis inhibitor for a variety of experimental and clinical applications.

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