From molecular design to synthesis: novel potential degraders for Tauopathies

Tauopathies, including Alzheimer's disease, constitute a heterogeneous group of neurodegenerative disorders characterized by progressive cognitive decline, personality changes and memory impairment. Among their hallmarks, the aggregation and hyperphosphorylation of the microtubule-associated protein tau play a central role, establishing this protein as a compelling target for therapeutic intervention. Given that aberrant tau species have been reported to trigger a broad spectrum of pathomechanisms, selectively addressing a single downstream pathway has proven insufficient to achieve meaningful therapeutic outcomes. Polypharmacological agents may overcome this limitation by concurrently modulating tau aggregation, tau phosphorylation, and additional tau-related functions that become impaired in the disease context. The adoption of polypharmacological strategies has indeed shown considerable advantages over conventional single-target approaches, especially when dealing with multifactorial disorders1. In a recent work published on Nature communication, the small molecule PHOX15 was identified as putative polypharmacological drug that interact with tau and modulate tau kinases GSK3β and Cdk5. They found that PHOX15 inhibits tau aggregation, restores tau’s physiological microtubule interaction, and reduces tau phosphorylation at disease-relevant sites2. In light of all these considerations, this research project aims to explore the potential of PHOX15 in the field of Targeted Protein Degradation (TPD)3,4. This group of innovative approaches enables the selective degradation of a protein of interest by exploiting the ubiquitin-proteasome system. In order to investigate the proposed idea, a computational study, incorporating molecular docking and molecular dynamics simulations (MDs), was conducted to identify a portion of PHOX15 suitable for the construction of the degraders. A small library of potential tau candidate degraders was subsequently designed, screened and evaluated through computational calculations. The most promising candidates are currently under development, and the design, synthesis and characterization will be presented and discussed.