Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States.
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States.
Bioorg Med Chem. 2018 Dec 1;26(22):5766-5779. doi: 10.1016/j.bmc.2018.10.009. Epub 2018 Oct 24.
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.
视黄醛脱氢酶（RALDH）酶，RALDH1、RALDH2 和 RALDH3，催化视黄醛不可逆氧化为全反式视黄酸（ATRA）。尽管 RALDH 酶在胚胎发育、出生后生长和分化以及几种疾病状态中具有重要作用，但目前还没有专门针对这些同工酶的商业上可获得的抑制剂。我们在这里报告了小分子抑制剂二氯全反式视黄酮（DAR）（Summers 等人，2017 年）的开发和表征，它是 RALDH1、2 和 3 的不可逆抑制剂，有效地在纳摩尔范围内抑制 RALDH1、2 和 3，但对线粒体 ALDH2 没有抑制活性。这些结果为将 DAR 开发为各种实验和临床应用的特定 ATRA 合成抑制剂提供了支持。
