GSK-3β and HDAC modulators as potential strategies to treat chronic-degenerative diseases

Alzheimer’s disease (AD) and cancer are chronic disorders with a progressive impact on daily life. Furthermore, both are degenerative: AD involves cognitive decline, while cancer entails loss of genomic and cellular control. AD affects over 50 million people worldwide, projected to reach 75 million by 2030. Cancer caused ~20 million new cases in 2022 and is expected to rise by over 77% by 2050. No effective therapy exists for AD, and cancer treatments are not universally effective. In light of this, this work addresses two main topics: the development of innovative anti-AD agents and potential anticancer agents. Glycogen synthase kinase-3β (GSK-3β) and histone deacetylase 6 (HDAC6) are two key enzymes implicated in AD pathology. Therefore, two series of dual GSK-3β/HDAC inhibitors were developed: one based on the ATP-competitive inhibitor AR-A014418, and the other on the non-ATP-competitive tideglusib, both incorporating hydroxamic acid for HDAC targeting. The results, recently published, identified promising hit compounds for developing innovative disease-modifying agents. Compared with enzymatic inhibition, targeted protein degradation offers enhanced selectivity and prolonged effects. Accordingly, this thesis also reports the design, synthesis, and preliminary evaluation of dual-target PROTACs against HDACs and GSK-3β, combining the benefits of a multi-target strategy with selective degradation via PROTAC-mediated E3 ligase recruitment. HDACs also play a key role in cancer, mainly via epigenetic regulation. Among them, HDAC11 is poorly characterized, and targeting it may help elucidate its function and therapeutic potential. Therefore, this work reports the synthesis of selective HDAC11 inhibitors, with the most potent one used as a scaffold for the synthesis of new HDAC11 PROTACs. A novel dual HDAC/G-quadruplex (G4) inhibitor was also designed to target epigenetic regulation and DNA secondary structures in telomeres and oncogene promoters, supporting a multi-target strategy. In general, preliminary results obtained support further development in AD, epigenetics, and cancer therapy.