CAMBRIDGE, Mass.--()--Proteostasis Therapeutics, Inc., a company developing novel therapeutics that regulate protein homeostasis to improve outcomes for patients with neurodegenerative and orphan diseases, today presented data supporting the Company’s protein clearance program in a poster titled “Developing Usp14 Inhibitors as Disease-Modifying Therapeutics for Protein Aggregation Diseases” at the 11th International Conference on Alzheimer’s and Parkinson’s Diseases in Florence, Italy.
“We are very encouraged by our results to date, as they support our development of these molecules as a disease-modifying approach for multiple neurodegenerative indications”
“Alzheimer’s, Parkinson’s and similar neurodegenerative diseases stem from the accumulation of misfolded proteins in the brain, specifically α-synuclein in Parkinson’s disease, amyloid-β and tau in Alzheimer’s disease and TDP-43 in ALS. We are pursuing a novel approach to stimulate proteasome-mediated clearance of these proteins by inhibiting the enzyme Usp14,” stated Peter Reinhart, Ph.D., President and Chief Scientific Officer of Proteostasis Therapeutics. “The data presented today show that our lead molecules modulate the Proteostasis Network to enhance the degradation of disease-relevant proteins and support the development of Usp14 inhibitors for protein aggregation diseases.”
Proteostasis Therapeutics has assembled an integrated platform to identify small molecules that modulate Proteostasis Network pathways, including those involving protein folding, trafficking, and clearance. The Company’s work in protein clearance focuses on enhancing proteasome-mediated degradation, which for certain proteins can be limited by proteasome-associated enzymes, such as Usp14.
The data presented today exemplify the application of the Company’s platform to identify and develop Usp14 inhibitors to enhance the clearance of disease-relevant protein aggregates, leading to the advancement of two chemical series with different mechanisms of action that are both potent and have tractable drug-like properties.
The data also show that the genetic knockdown of Usp14 resulted in the lowering of soluble α-synuclein in cellular and neuronal models. Compound-mediated lowering of α-synuclein was observed in various cellular models including iPS neurons, as well as a decrease of soluble tau with Usp14 knockdown or inhibition in various cellular and neuronal models. This compound from the lead series was well tolerated in vivo, showing no overt toxicity and high free brain exposures in rats.
“We are very encouraged by our results to date, as they support our development of these molecules as a disease-modifying approach for multiple neurodegenerative indications,” Reinhart stated. “We look forward to advancing our Usp14 inhibitor compounds through lead optimization and toward candidate nomination this year.”
About Proteostasis Therapeutics
Proteostasis Therapeutics is developing disease-modifying therapeutics for orphan and neurodegenerative diseases. The Company’s lead programs in Cystic Fibrosis (CF) and protein aggregation diseases such as Parkinson’s disease modulate protein chaperone and proteasomal degradation pathways within the cell. These pathways are part of the cellular ‘quality control’ machinery, called the protein homeostasis network or Proteostasis Network (PN) that regulates protein folding, trafficking, and clearance. By enhancing the function and capacity of the PN, the Company’s product candidates correct for imbalances in the PN resulting from the cumulative effects of disease, genetic mutations, environmental factors, and aging. For more information, please visit www.proteostasis.com.