SMALL MOLECULES
Contributor Information
- Name Laurent Rigoreau
- Institute Cancer Research Technology
Tool Details
- Tool name: AKR1C3 inhibitor CRT0036521 Small Molecule (Tool Compound)
- Molecular formula: C16H15NO4S
- Tool type: Small molecules
- Tool sub-type: Inhibitor
- Purpose: Inhibitor
- Molecular weight of the target: 317.37
- Application: The compounds showed good cellular potency, as measured by inhibition of AKR1C3 metabolism of a known dinitrobenzamide substrate, with a broad rank order between enzymic and cellular activity, but amide analogues were more effective than predicted by the cellular assay. displays potency in a cellular assay, blocking the ability of AKR1C3 to metabolize a proven substrate.
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Description: CRT0036521 is a highly potent and selective inhibitor of the Type 5 17-?-Hydroxysteroid. A high-throughput screen identified 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acid as a novel, highly potent (low nM), and isoform-selective (1500-fold) inhibitor of aldo-keto reductase AKR1C3: a target of interest in both breast and prostate cancer. Crystal structure studies showed that the carboxylate group occupies the oxyanion hole in the enzyme, while the sulfonamide provides the correct twist to allow the dihydroisoquinoline to bind in an adjacent hydrophobic pocket. SAR studies around this lead showed that the positioning of the carboxylate was critical, although it could be substituted by acid isosteres and amides. Small substituents on the dihydroisoquinoline gave improvements in potency. A set of
- Research area: Cell Signaling & Signal Transduction; Metabolism; Neurobiology
- Selectivity: Isoform-selective (1500-fold) inhibitor of aldo-keto reductase AKR1C3. Does not display any COX (cyclooxygenase) inhibition at 10 ÂľM in whole blood assay.
- IUPAC: 3â(3,4-Dihydroisoquinolin-2(1H)âylsulfonyl)benzoic Acid
- IC50: IC50 of 0.013 Âą 0.003 ÎźM for AKR1C3, compared with 20.3 Âą 3.8 ÎźM against AKR1C1 and >30 ÎźM against AKR1C2 and AKR1C4.
- For Research Use Only
Target Details
- Target molecular weight: 317.37
- Primary target: AKR1C3
Application Details
- Application: The compounds showed good cellular potency, as measured by inhibition of AKR1C3 metabolism of a known dinitrobenzamide substrate, with a broad rank order between enzymic and cellular activity, but amide analogues were more effective than predicted by the cellular assay. displays potency in a cellular assay, blocking the ability of AKR1C3 to metabolize a proven substrate.
Handling
- Purity: 317.37 g/mol
- Shipping conditions: Dry Ice
Documentation
- Available on request
Related Tools
References
- • Janieson et al. 2012. J Med.Chem. PMID: 22877157
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