title: Design, synthesis and evaluation of caffeic acid phenethyl ester-based inhibitors targeting a selectivity pocket in the active site of human aldo-keto reductase 1B10.
abstract: Inhibitors of a human aldo-keto reductase, AKR1B10, are regarded as promising therapeutics for the treatment of cancer, but those with both high potency and selectivity compared to the structurally similar aldose reductase (AKR1B1) have not been reported. In this study, we have found that, among honeybee propolis products, caffeic acid phenethyl ester (CAPE) inhibited AKR1B10 (IC(50) = 80 nM) with 7-fold selectivity over AKR1B1. Based on a model of docked CAPE in AKR1B10, its derivatives were designed, synthesized and evaluated for inhibitory potency. Among them, 3-(4-hydroxy-2-methoxyphenyl)acrylic acid 3-(3-hydroxyphenyl)propyl ester (10c) was the most potent competitive inhibitor (K(i) = 2.6 nM) with 790-fold selectivity for AKR1B10 over AKR1B1. Molecular docking of 10c and site-directed mutagenesis of AKR1B10 residues suggested that the interactions between the 2-methoxy and 3-hydroxy groups of 10c and the enzyme's Val301 and Gln114, respectively, are important for the inhibitor's selectivity. Additionally, the sub-μM concentration of 10c significantly suppressed the farnesal metabolism and cellular proliferation in AKR1B10-overexpressing cells.
authors.affiliation: Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Soda
authors.forename: Dawei
authors.initials: D
authors.lastname: Hu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Mayuko
authors.initials: M
authors.lastname: Takemura
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Ryogo
authors.initials: R
authors.lastname: Wada
authors.forename: Syohei
authors.initials: S
authors.lastname: Ifuku
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Zhao
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.forename: Shozo
authors.initials: S
authors.lastname: Ohta
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamura
authors.forename: Naoki
authors.initials: N
authors.lastname: Toyooka
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000074408:Aldo-Keto Reductases; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002109:Caffeic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D011429:Propolis / Q000737:chemistry* / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D002109:Caffeic Acids; D004791:Enzyme Inhibitors; D011429:Propolis; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase