Aitken Laura, Baillie Gemma, Pannifer Andrew, Morrison Angus, Major Louise L, Alphey Magnus S, Sethi Ritika, Timmerman Martin, Robinson John, Riley Jennifer, Shishikura Yoko, Koekemoer Lizbe, Von Delft Frank, Rutjes Helma, Read Kevin D, Jones Philip S, McElroy Stuart P, Smith Terry K, Gunn-Moore Frank J
University of St. Andrews School of Chemistry, Biomolecular Sciences Building, North Haugh, St. Andrews KY16 9TF, U.K.
BioAscent Discovery Ltd, Bo'Ness Road, Newhouse, Lanarkshire ML1 5UH, U.K.
ACS Chem Biol. 2025 Jul 18;20(7):1544-1559. doi: 10.1021/acschembio.5c00110. Epub 2025 Jun 18.
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 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.
在本研究中，展示了首次针对近35万个类药物分子进行的工业规模高通量筛选，这些分子靶向17β-HSD10酶，该酶是阿尔茨海默病和癌症的一个有前景的治疗靶点。鉴定出了两个新型系列的强效17β-HSD10抑制剂，它们在酶和细胞试验中均表现出低纳摩尔效力，且细胞毒性最小。通过一系列证明配体-蛋白质相互作用和共结晶学的试验对这些抑制剂进行了进一步表征，结果显示与之前发表的抑制剂不同，它们对辅因子NADH表现出非竞争性抑制。这项工作显著推动了靶向17β-HSD10的治疗药物的开发，为治疗阿尔茨海默病和癌症提供了新的潜在先导化合物。
