Development ofN-acyl Fluspirilene 20S Proteasome Enhancers for the Treatment of Neurodegenerative Diseases

Abstract ID 131514 Poster Board 295 Currently, there are limited therapeutic treatments to slow, prevent, or cure neurodegenerative diseases such as Alzheimer's Disease or Alzheimer's-related Dementias.¹ These diseases are characterized by an accumulation of oligomerized intrinsically disordered proteins (IDPs) and impairment of 20S proteasome-mediated protein degradation.²–⁴ In 2021, our group conducted a high-throughput screen of the NIH Clinical Collection and Prestwick libraries and identified FDA-approved drug fluspirilene and its analogue N-acyl fluspirilene as a class of small molecules capable of enhancing 20S proteasome-mediated IDP degradation, overcoming IDP-induced 20S proteasome impairment, and degrading intrinsically disordered proteins.⁵ This project aims to expand on the published computational, synthetic, and biological efforts to (1) identify the pivotal structural features of the N-acyl fluspirilene class necessary for 20S proteasome activation, (2) rationally develop improved 20S proteasome enhancers, and (3) overcome 20S proteasome impairment induced by IDP oligomers. Successful completion of this work will enable the rapid design, development, and identification of 20S proteasome activators, and elucidate the role of 20S proteasome modulation in neurodegenerative diseases as a novel therapeutic strategy for disease treatment. Bibliography: Institute on Aging, N. NIH Scientific Progress Report, 2022. Advancing Alzheimer's Disease and Related Dementias Research for All Populations. 2022. Zondler, L.; Kostka, M.; Garidel, P.; Heinzelmann, U.; Hengerer, B.; Mayer, B.; Weishaupt, J. H.; Gillardon, F.; Danzer, K. M. Proteasome Impairment by α-Synuclein. PLoS One2017, 12 (9). Keller, J. N.; Hanni, K. B.; Markesbery, W. R. Impaired Proteasome Function in Alzheimer's Disease. J Neurochem2000, 75 (1), 436–439. Thibaudeau, T. A.; Anderson, R. T.; Smith, D. M. A Common Mechanism of Proteasome Impairment by Neurodegenerative Disease-Associated Oligomers. Nature Communications 2018 9:12018, 9 (1), 1–14. Fiolek, T. J.; Keel, K. L.; Tepe, J. J. Fluspirilene Analogs Activate the 20S Proteasome and Overcome Proteasome Impairment by Intrinsically Disordered Protein Oligomers. ACS Chem Neurosci2021, 12 (8), 1438–1448.