UC San Diego

Misfolded alpha-synuclein has been identified as a potential target to developing disease modifying or preventative therapies for Parkinson’s Disease. Proteolytic Targeting Chimeras (PROTACs) have been demonstrated as chemical tools and selective degraders for protein targets in neurodegenerative diseases. PROTACs have already been demonstrated as chemical tools and selective degraders for other neurodegenerative diseases such as targeting tau protein for Frontal Temporal Dementia. Taking previously known binders of alpha-synuclein and proteasomal ligand recruiters a library of PROTACs was synthesized in addition to small molecule degraders with a guanosine-derived autophagy tag, or Autophagy Targeting Chimera (AUTAC), as an alternative form of degradation. Successful development of a selective and potent degrader would allow a better understanding of alpha-synuclein and its role in Parkinson’s Disease.

Hyperphosphorylation of Tau is a hallmark of many neurodegenerative diseases. Tau Tubulin Kinase 1 (TTBK1) is involved in tau phosphorylation and has been indicated to phosphorylate tau at pathologically relevant sites making it a promising drug target. Small molecule inhibitors exist that can inhibit TTBK1 with off target affects on TTBK2 which has important functions throughout the nervous system. Utilizing known crystal structures of TTBK1 and TTBK2, selective small molecules were synthesized taking advantage of a peripheral lysine residue which can covalently react with a flour sulfonyl moiety. Using this strategy, separation of TTBK1 and 2 would allow for detailed understanding of their separate and overlapping substrates and biological functions.