Structural Determinants of the Selectivity of 3‐Benzyluracil‐1‐acetic Acids toward Human Enzymes Aldose Reductase and AKR1B10

Abstract

The human enzymes aldose reductase (AR) and AKR1B10 have been thoroughly explored in terms of their roles in diabetes, inflammatory disorders, and cancer. In this study we identified two new lead compounds, 2-(3-(4-chloro-3-nitrobenzyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (JF0048, 3) and 2-(2,4-dioxo-3-(2,3,4,5-tetrabromo-6-methoxybenzyl)-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (JF0049, 4), which selectively target these enzymes. Although 3 and 4 share the 3-benzyluracil-1-acetic acid scaffold, they have different substituents in their aryl moieties. Inhibition studies along with thermodynamic and structural characterizations of both enzymes revealed that the chloronitrobenzyl moiety of compound 3 can open the AR specificity pocket but not that of the AKR1B10 cognate. In contrast, the larger atoms at the ortho and/or meta positions of compound 4 prevent the AR specificity pocket from opening due to steric hindrance and provide a tighter fit to the AKR1B10 inhibitor binding pocket, probably enhanced by the displacement of a disordered water molecule trapped in a hydrophobic subpocket, creating an enthalpic signature. Furthermore, this selectivity also occurs in the cell, which enables the development of a more efficient drug design strategy: compound 3 prevents sorbitol accumulation in human retinal ARPE-19 cells, whereas 4 stops proliferation in human lung cancer NCI-H460 cells.

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

“…The polyhalogenated compound is characterized as a novel lead, a tetrafluorophenol moiety that targets both AKR1B10 and AR. The same group also solved the methylated AKR1B10K125R/V301L-sulindac complex, which showed that sulindac ( 34 ) and its sulfone might be a drug lead for selective AKR1B10 and AR inhibitors [32], and the methylated AKR1B10K125R/V301L-JF0049, which explained that the selectivity of JF0049 ( 30 ) for AKR1B10 is probably due to its bulkier aryl moiety that cannot occupy the AR specificity pocket but fitting into the larger AKR1B10 active site, including a subpocket defined by loop A that does not exist in AR [36]. These studies collectively pave the way for future efforts in structure-guided drug discovery to target AKR1B10.…”

“…the acidic phenol) [35]. JF0049 is found to be selective for AKR1B10, which is probably due to its bulkier aryl moiety unable to occupy the AR specificity pocket and its improved fitting into the larger AKR1B10 active site, including a 
subpocket defined by loop A [36]. The application of 
5-carboxymethyl-3-mercapto-1,2,4-triazino-[5,6-B]indoles (WO2015057175) [121], and drug composition containing this compounds was due to their ability to inhibit AKR1B1 and AKR1B10.…”

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

“…It can be used as a selective inhibitor of AKR1B10. Newly, two synthesized polyhalogenated compound 2,2 ,3,3 ,5,5 ,6,6 -octafluoro-4,4 -biphenyldiol (JF0064, 29) and 2-(2,4-dioxo-3-(2,3,4,5-tetrabromo-6-methoxybenzyl)-3,4-dihydropyrimidin-1(2H)-yl) acetic acid (JF0049, 30) were reported to be potent AKR1B10 inhibitors [35,36]. JF0064 is a non-competitive inhibitor for both AR and AKR1B10.…”

“…The development of potent and selective AKR1B10 inhibitor as anticancer drugs has attracted growing attentions. Recently, many AKR1B10 inhibitors have been developed rapidly [24][25][26][27][28][29][30][31][32][33][34][35][36][37]. We here, review the recent publications and patents related to AKR1B10 inhibitors.…”

Efficacy of aldose reductase inhibitors is affected by oxidative stress induced under X-ray irradiation

“…This modification has been characterized by enzymatic assays after exposition of hAR in solution under different irradiation doses, by monitoring the progressive structural changes of hAR crystals as irradiation dose increases and by characterizing the structural changes in solution using mass spectrometry. The activity of the in-vitro potent ARIs Zenarestat 30 , JF0048 31 , Epalrestat 32 and Tolrestat 33 was also checked at different irradiation doses. A mechanism for the activation of hAR under oxidative stress conditions is proposed and some suggestions for the structure-based drug design targeting hAR are provided.…”