Patent Highlights: Allosteric AR Modulators, Glycogen Synthase Inhibitors, and More

This article highlights million-dollar molecules that were recently in the news with related patent applications that give clues to their structures and properties. This edition includes Maze’s glycogen synthase 1 (GYS1) inhibitors that were recently licensed to Sanofi, allosteric androgen receptor (AR) modulators that may be of interest to targeted protein degradation researchers, brain-penetrant HER2 and ROCK2 inhibitors, and MDM2 degraders.

Maze’s Oral GYS1 Inhibitor, MZE001

Sanofi is paying $150 million plus up to $600 million in milestones for Maze Therapeutics’ glycogen synthase 1 (GYS1) program, including MZE001, which aims to reduce glycogen substrate build-up in Pompe disease. Pompe disease is a glycogen storage disease caused by mutations in alpha-glucosidase, leading to pathological glycogen accumulation across tissues including skeletal and cardiac muscle. If the molecule reaches approval, MZE001 could be the first oral therapy for Pompe disease, either alone or in combination with enzyme-replacement therapy. While MZE001’s structure has not been disclosed, an arbitrarily-selected representative example from a recently published patent is highlighted below.

Maze Therapeutics’ oral glycogen synthase 1 inhibitor, MZE001, recently completed a phase 1 trial (NCT05249621; n=121; single ascending dose) showing the drug was well tolerated at doses up to 720 mg BID for 10 days (1 mild or moderate drug-related effect) and lowered glycogen levels, showing that the drug achieved target engagement. According to a company presentation, the 480 mg BID dose covers the ~paEC50 (~650 ng/mL) for >24 h, with a half-life of 12 hours.

Evidence for the target comes from human genetics showing that loss of function of PPP1R3A, a key activator of muscle GYS1 that dephosphorylates GYS1, leads to reduction in muscle glycogen. Meanwhile, genetic association studies in humans show that the same protein-truncating variants (PTVs) in the PPP1R3A gene that lead to ~65% reduction in muscle glycogen in humans do not affect cardiac parameters including left ventricle wall thickness, left ventricular ejection fraction, exercise output, maximum heart rate, QT interval, or serum glucose, suggesting that target inhibition could be well-tolerated.

Maze filed a patent for potent and selective inhibitors of GYS1 in 2022 (WO2022198196) as well as the method of use, with inventors including Maze’s GYS program leader and Associate Director of Medicinal Chemistry, Kevin Mellem, Head of Chemistry, Chris Sinz, EVP of Drug Discovery, David Morgans, Head of Computational Chemistry, Patrick Lee, and additional current & former Maze team members, Hannah Powers, and Walter Won.

Oral Allosteric AR Modulators