Design, Facile Synthesis, and Evaluation of a Chalcone-Based Small Molecule ULK1 Agonist for the Treatment of Huntington’s Disease

Overview

Huntington’s Disease (HD) is a fatal neurodegenerative disorder caused by a mutation in the huntingtin gene (HTT). This abnormal sequence codes for a mutated version of the huntingtin protein which accumulates as aggregates in neuronal cells, leading to ne urological decline, disability, and death. Currently, no cure exists for HD and treatment consists of symptom management and supportive care. Studies have shown that using autophagy to clear mutated HTT protein aggregates may be a potential curative treatm ent option. The initiation of the autophagic process is mediated by the ULK1 complex. Previous research has demonstrated that pharmacologic agents can agonize this complex to clear protein aggregates, producing neuroprotective effects. This research aims t o computationally design, synthesize, and evaluate a novel drug that improves upon these capabilities. Using computational modeling, a promising candidate with a chalcone pharmacore, B-21, was identified that shows improved docking at the activation site compared to a known ULK1 agonist and exhibits favorable pharmacological properties. This candidate was successfully synthesized, as determined by H-NMR, FTIR, and melting point analysis. This compound was then evaluated in a biological yeast model and it wa s determined that B -21 induces autophagy in that model. Together, these results demonstrate that B-21 is a potential therapeutic agent for promoting autophagy and clearing protein aggregates in the context of HD remediation.

Competition history

• JSHS 2024 Category not listed

Resources

• National JSHS abstract book ↗

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