Biochemical and physiological importance of the CYP26 retinoic acid hydroxylases

Retinoic acid (RA), the active metabolite of vitamin A, is an important endogenous signaling molecule regulatingcell cycle and maintenance of epithelia. RA isomers are also used as drugs to treat various cancers and dermatologicaldiseases. However, the therapeutic uses of RA isomers are limited due to side effects such as teratogenicity and resistanceto treatment emerging mainly from autoinduction of RA metabolism. To improve the therapeutic usefulness of retinoids,RA metabolism blocking agents (RAMBAs) have been developed. These inhibitors generally target the cytochrome P450(CYP) enzymes because RA clearance is predominantly mediated by P450s. Since the initial identification of inhibitors ofRA metabolism, CYP26 enzymes have been characterized as the main enzymes responsible for RA clearance. This makesCYP26 enzymes an attractive target for the development of novel therapeutics for cancer and dermatological conditions.The basic principle of development of CYP26 inhibitors is that endogenous RA concentrations will be increased in thepresence of a CYP26 inhibitor, thus, potentiating the activity of endogenous RA in a cell-type specific manner. This willreduce side effects compared to administration of RA and allow for more targeted therapy. In clinical trials, inhibitors ofRA metabolism have been effective in treatment of psoriasis and other dermatological conditions as well as in some cancers.However, no CYP26 inhibitor has yet been approved for clinical use. This review summarizes the history of developmentof RAMBAs, the clinical and preclinical studies with the various structural series and the available knowledge ofstructure activity relationships of CYP26 inhibitors.

/pdf/therapeutic-potential-of-the-inhibition-of-the-retinoic-acid-1djgb9bdi5.pdf

Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

Design, synthesis, and biological evaluation of amide imidazole derivatives as novel metabolic enzyme CYP26A1 inhibitors

Stereoselective Formation and Metabolism of 4-Hydroxy-Retinoic Acid Enantiomers by Cytochrome P450 Enzymes

Synthesis and biological evaluation of 3-phenyl-3-aryl carboxamido propanoic acid derivatives as small molecule inhibitors of retinoic acid 4-hydroxylase (CYP26A1).

Two three-dimensional (3D) models of human cytochrome P450 26A1 (CYP26A1) were constructed using the programs Modeller and Sybyl-GeneFold, respectively. After refinement by molecular mechanics and molecular dynamics (MD) simulations, the two models were validated by structure analysis-validation online server. Subsequently, a flexible docking study was performed on the model constructed by GeneFold with the potent and specific inhibitor R115866 to examine the enzyme–inhibitor interactions. From the docking results, we can see R115866 interacts with amino acid residues at the active site by multiple hydrophobic interactions including the side chains of His111, Trp112, Ser115, Val116, Leu125, Ser126, Leu221, Phe222, Glu296, Phe299, Gly300, Glu303, Thr304, Pro371 and the cofactor heme. Trp112 and Thr304 form hydrogen bonds with R115866 and play important roles in stabilising the complex. This constructed CYP26A1 model may provide an opportunity to understand the action mode of the enzyme and could be useful ...

Structure prediction and R115866 binding study of human CYP26A1: homology modelling, fold recognition, molecular docking and MD simulations

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Structure prediction and R115866 binding study of human CYP26A1: homology modelling, fold recognition, molecular docking and MD simulations