2 research outputs found
3‑(3,4-Dihydroisoquinolin-2(1<i>H</i>)‑ylsulfonyl)benzoic Acids: Highly Potent and Selective Inhibitors of the Type 5 17-β-Hydroxysteroid Dehydrogenase AKR1C3
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 “reverse sulfonamides” showed a 12-fold preference
for the <i>R</i> stereoisomer. 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
Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3
A weak
screening hit with suboptimal physicochemical properties was optimized
against PFKFB3 kinase using critical structure-guided insights. The
resulting compounds demonstrated high selectivity over related PFKFB
isoforms and modulation of the target in a cellular context. A selected
example demonstrated exposure in animals following oral dosing. Examples
from this series may serve as useful probes to understand the emerging
biology of this metabolic target