Development of glycogen synthase inhibitors for APBD
Awardee: Wyatt Yue
Institution: Newcastle University
Grant Amount: $56,857
Funding Period: February 1, 2025 - January 31, 2026
Summary:
In APBD, the defective branching enzyme GBE1 results in malformed glycogen being synthesised by glycogen synthase GYS1 to form clogging clumps. Drug development programmes for APBD and related diseases have largely sought to deliver an artificial version of the GBE1 gene, or turn down the native GYS1 gene, to mitigate the consequences in the disease. Our vision is to develop a daily pill of GYS1 small molecule inhibitor for APBD patients as a transformative oral therapy. Thanks to previous Million Dollar Bike Ride grant funding, we set up an innovative screening method to identify small molecule ‘hits’ that act on GYS1, which is now running. Building upon this, this project will systematically work through hits identified, to validate their mode of action and optimise the molecules to have the necessary drug-like properties including brain penetration. We will achieve this taking advantage of our unique knowhow on the GYS1 protein, as well as cutting-edge computational and chemistry expertise.