Neurodegenerative diseases, such as Alzheimer's and Parkinson's, affect millions worldwide. Despite their prevalence, these patients have limited treatment options, with therapeutics prescribed mainly to alleviate symptoms and not target disease progression. One of the key pathological pathways observed in neurodegeneration is the aggregation of Intrinsically Disordered Proteins (IDPs). IDPs, such as α-synuclein, are difficult to target due to their disordered nature. The use of small molecule 20S proteasome activators has been identified as a potential pathway to target these pathological IDPs indirectly. However, potent small molecule 20S proteasome activators are scarce, hampering the detailed evaluation of this potential therapeutic strategy. Previously, we identified analogs of the FDA-approved Chlorpromazine bearing a bis(fluorophenyl) amide tail as efficient 20S proteasome activators and increased the proteolytic degradation of α-synuclein in both in vitro and cellular studies. Herein, we report synthesizing and evaluating twenty-six small molecules containing the bis(fluorophenyl)amide tail coupled with different heterocyclic cores as 20S proteasome activators. In purified enzymatic assays, two novel analogs were identified as sub-micromolar 20S proteasome activators. The observed potency translates in a cellular model; both analogs significantly increased the proteolytic degradation of the A53T mutant α-synuclein at concentrations below 1 µM, preventing the accumulation of this toxic protein in HEK-293T cells. The potency exhibited by these two molecules will allow for the evaluation of 20S proteasome activation in disease-relevant models and mark significant progress in developing 20S proteasome activators as potential.

Potent Bis(fluorophenyl) amide-based small molecule 20S proteasome activators enhance proteolytic degradation of A53T α-synuclein in cells

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