Identification of a novel polyfluorinated compound as a lead to inhibit the human enzymes aldose reductase and AKR1B10: structure determination of both ternary complexes and implications for drug design

Abstract

Aldo-keto reductases (AKRs) are mostly monomeric enzymes which fold into a highly conserved (α/β)8 barrel, while their substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable external loops. The closely related human enzymes aldose reductase (AR or AKR1B1) and AKR1B10 are of biomedical interest because of their involvement in secondary diabetic complications (AR) and in cancer, e.g. hepatocellular carcinoma and smoking-related lung cancer (AKR1B10). After characterization of the IC50 values of both AKRs with a series of polyhalogenated compounds, 2,2',3,3',5,5',6,6'-octafluoro-4,4'-biphenyldiol (JF0064) was identified as a lead inhibitor of both enzymes with a new scaffold (a 1,1'-biphenyl-4,4'-diol). An ultrahigh-resolution X-ray structure of the AR-NADP(+)-JF0064 complex has been determined at 0.85 Å resolution, allowing it to be observed that JF0064 interacts with the catalytic residue Tyr48 through a negatively charged hydroxyl group (i.e. the acidic phenol). The non-competitive inhibition pattern observed for JF0064 with both enzymes suggests that this acidic hydroxyl group is also present in the case of AKR1B10. Moreover, the combination of surface lysine methylation and the introduction of K125R and V301L mutations enabled the determination of the X-ray crystallographic structure of the corresponding AKR1B10-NADP(+)-JF0064 complex. Comparison of the two structures has unveiled some important hints for subsequent structure-based drug-design efforts.

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

“…Nevertheless, only 13 different crystallographic structures of AKR1B10 have been released (Table 1 ). AKR1B10 and AR have different substrate specificity and inhibitor selectivity mainly due to residue differences in their three external and variable loops [35]. …”

“…By using the surface lysine methylation (SLM) technique, that can improve the success rate of protein crystallization by chemically methylating lysine residues, Cousido-Siah et al solved the structure of the methylated AKR1B10K125R/V301L-JF0064 ( 29 ) complex [35]. The polyhalogenated compound is characterized as a novel lead, a tetrafluorophenol moiety that targets both AKR1B10 and AR.…”

“…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.…”

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

“…By using the surface lysine methylation (SLM) technique, that can improve the success rate of protein crystallization by chemically methylating lysine residues, CousidoSiah et al solved the structure of the methylated AKR1B10K125R/V301L-JF0064 (29) complex [35]. The polyhalogenated compound is characterized as a novel lead, a tetrafluorophenol moiety that targets both AKR1B10 and AR.…”

“…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.…”