Virtual Screening Identifies Inhibitors and First-in-Class Activators of 17β-Hydroxysteroid Dehydrogenase Type 10

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in individuals over the age of 65, there remains a critical need for new therapeutic discovery that can treat the underlying cause of the disease.The enzyme 17-hydroxysteroid dehydrogenase type 10 (17-HSD10) has numerous substrates and multiple roles within the mitochondria.The enzyme has been linked to a role in multiple cancers; however, the majority of research has been focused on its role in AD due to its binding to the AD hallmark protein amyloid beta (A).The interaction of 17-HSD10 and A leads to disruption of the enzyme's structure and function, potentiating A toxicity and resulting in mitochondrial dysfunction and cell death through a myriad of pathways.Significant effort has focused on identifying small molecules that can disrupt the interaction of A with 17-HSD10 to restore mitochondrial homeostasis and protect against the toxicity.However, these molecules are limited to approximately five chemotypes, which all suffer from pharmacokinetic liabilities.Herein, we describe the use of virtual screening to identify new modulators of 17-HSD10 that are structurally dissimilar to known chemotypes.Five hit compounds were selected based on their ability to meet or exceed defined metrics.These compounds were synthesized and evaluated for their ability to modulate 17-HSD10 and protect against A-induced toxicity.From this work, we report three new inhibitor chemotypes of 17-HSD10 for further development in AD drug discovery.Additionally, we identified the first activators of 17-HSD10 which represent valuable chemical probes to investigate the effect of 17-HSD10 activation on its downstream pathway.predicted to be more likely to cross the BBB.For an early-stage CNS drug discovery project, progressing compounds that achieve a CNS MPO score greater than 3 eliminates restrictions in SAR studies.