Evaluation of compound selectivity of aldo-keto reductases using differential scanning fluorimetry

Inhibitors of AKR1B10 belonging to the aldo-keto reductase (AKR) superfamily are considered promising candidates for anti-cancer drugs. AKR1B1, a structurally similar isoform of AKR1B10, is involved in glucose metabolism. Thus, selective inhibition of AKR1B10 is required for the development of anti-...

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Bibliographic Details
Published in:Journal of biochemistry (Tokyo) 2017-02, Vol.161 (2), p.215-222
Main Authors: Kabir, Aurangazeb, Endo, Satoshi, Toyooka, Naoki, Fukuoka, Mayuko, Kuwata, Kazuo, Kamatari, Yuji O
Format: Article
Language:English
Subjects:
Aldehyde Reductase - antagonists & inhibitors
Aldehyde Reductase - chemistry
Aldehyde Reductase - metabolism
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Enzyme Assays - methods
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Fluorometry - methods
Humans
Isoenzymes - antagonists & inhibitors
Isoenzymes - classification
Isoenzymes - genetics
Models, Chemical
Models, Molecular
Molecular Structure
Phylogeny
Protein Domains
Reproducibility of Results
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Summary:Inhibitors of AKR1B10 belonging to the aldo-keto reductase (AKR) superfamily are considered promising candidates for anti-cancer drugs. AKR1B1, a structurally similar isoform of AKR1B10, is involved in glucose metabolism. Thus, selective inhibition of AKR1B10 is required for the development of anti-cancer drugs. In this study, we first compared correlations between melting temperature and the 50% inhibition concentration obtained from differential scanning fluorimetry (DSF) and an enzyme inhibitory experiment, respectively, and a good correlation was found, except for compounds with low solubility. This result indicates that the DSF method is useful for drug screening for the AKR superfamily. We then evaluated their selectivity as inhibitors against all seven major human AKR1 family proteins and found that C18 is most specific for AKR1B10.
ISSN:0021-924X
1756-2651
DOI:10.1093/jb/mvw063