Aitken L., Baillie G., Pannifer A., Morrison A., Major LL., Alphey MS., Sethi R., Timmerman M., Robinson J., Riley J., Shishikura Y., Koekemoer L., Von Delft F., Rutjes H., Read KD., Jones PS., McElroy SP., Smith TK., Gunn-Moore FJ.

In this study, the first industrial-scale high-throughput screening of nearly 350,000 drug-like molecules targeting the enzyme 17β-HSD10, a promising therapeutic target for Alzheimer's disease and cancers, is presented. Two novel series of potent 17β-HSD10 inhibitors that demonstrate low nanomolar potency against both the enzyme and in vivo cellular assays with minimal cytotoxicity were identified. These inhibitors were characterized further through a series of assays demonstrating ligand-protein interactions and co-crystallography, revealing un-/non-competitive inhibition with respect to the cofactor NADH, unlike previously published inhibitors. This work significantly advances the development of 17β-HSD10-targeting therapeutics, offering new potential leads for treating Alzheimer's disease and cancers.

High-Throughput Screening of Potent Drug-like Molecules Targeting 17β-HSD10 for the Treatment of Alzheimer's Disease and Cancer.

Aitken L., Baillie G., Pannifer A., Morrison A., Major LL., Alphey MS., Sethi R., Timmerman M., Robinson J., Riley J., Shishikura Y., Koekemoer L., Von Delft F., Rutjes H., Read KD., Jones PS., McElroy SP., Smith TK., Gunn-Moore FJ.

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