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

Angelica R Harper; Anh T Le; Timothy Mather; Anthony Burgett; William Berry; Jody A Summers

doi:10.1016/j.bmc.2018.10.009

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. Epub 2018 Oct 24.

Authors

Angelica R Harper¹, Anh T Le², Timothy Mather³, Anthony Burgett², William Berry¹, Jody A Summers⁴

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: jody-summers@ouhsc.edu.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Aldehyde Dehydrogenase / antagonists & inhibitors*
Aldehyde Dehydrogenase / metabolism
Aldehyde Dehydrogenase 1 Family
Aldehyde Oxidoreductases / antagonists & inhibitors*
Aldehyde Oxidoreductases / metabolism
Animals
Cells, Cultured
Chickens
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HEK293 Cells
Humans
Kinetics
Male
Models, Molecular
Molecular Structure
Retinal Dehydrogenase / antagonists & inhibitors*
Retinal Dehydrogenase / metabolism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Aldehyde Oxidoreductases
Aldehyde Dehydrogenase 1 Family
Aldehyde Dehydrogenase
ALDH1A1 protein, human
ALDH1A2 protein, human
Retinal Dehydrogenase
aldehyde dehydrogenase (NAD(P)+)

Abstract

Publication types

MeSH terms

Substances

Grants and funding