The Design, Synthesis and Biological Evaluation of Novel 17β-Hydroxysteroid Dehydrogenase Modulators

Alzheimer’s disease (AD), affecting over 55 million people globally, is projected to impact 150 million by 2050. With no cure available, current treatments mainly manage symptoms or slow disease progression. The need for therapies addressing the underlying mechanisms of AD is urgent. The primary hallmarks of AD are amyloid beta (Aβ) plaques, tau neurofibrillary tangles, mitochondrial dysfunction, and neuroinflammation, which coincide and worsen over time. 17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a mitochondrial enzyme involved in energy regulation, steroid metabolism, and cellular homeostasis, and its upregulation has been implicated in AD and various cancers. In AD, 17β-HSD10 exacerbates Aβ toxicity by binding to Aβ and disrupting neuronal function. Moreover, its overexpression, independent of Aβ interaction, contributes to reduced cellular energy and heightened cytotoxicity. These findings suggest that targeting 17β-HSD10 may offer a novel therapeutic strategy for AD, either by disrupting its Aβ interaction or inhibiting the enzyme itself. Several small molecule chemotypes have been identified to modulate 17β-HSD10, and although varying in shape, they all struggle when it comes to their pharmacokinetic (PK) properties, which, when progressed, will limit their efficacy. Therefore, developing current chemotypes to alleviate these liabilities and identifying new chemotypes to probe the restraints of the chemical space is fundamental to progressing this research. This work described details the design and synthesis of derivatives of AG18051, the most studied modulator of 17β-HSD10, building on prior structure-activity relationship studies to identify more potent and PK-friendly compounds. Additionally, a high-throughput screen led to the discovery of BCC0100281, a novel small molecule modulator of 17β-HSD10. A synthetic route for BCC0100281 and related derivatives was developed, followed by biological evaluation. To conclude this work, the process of virtual screening, hit evaluation, synthesis, and biological assessment will be described as a method to identify new modulator chemotypes with improved properties to be advanced in this area. The findings from this research contribute to the growing pool of potential small molecule modulators of 17β-HSD10. These molecules can be used to further investigate the relationship between 17β-HSD10 and AD (or cancer) and be developed into therapeutic candidates.