O-GlcNAcase Inhibitor ASN90 is a Multimodal Drug Candidate forTau and?-Synuclein Proteinopathies

Neurodegenerative proteinopathies are character-ized by the intracellular formation of insoluble and toxic proteinaggregates in the brain that are closely linked to diseaseprogression. In Alzheimer's disease and in rare tauopathies,aggregation of the microtubule-associated tau protein leads tothe formation of neurofibrillary tangles (NFT). In Parkinson'sdisease (PD) and other alpha-synucleinopathies, intracellular Lewybodies containing aggregates of alpha-synuclein constitute thepathological hallmark. Inhibition of the glycoside hydrolase O-GlcNAcase (OGA) prevents the removal of O-linkedN-acetyl-D-glucosamine (O-GlcNAc) moieties from intracellular proteins andhas emerged as an attractive therapeutic approach to prevent theformation of tau pathology. Like tau,alpha-synuclein is known to bemodified with O-GlcNAc moieties andin vitrothese have been shown to prevent its aggregation and toxicity. Here, we report thepreclinical discovery and development of a novel small molecule OGA inhibitor, ASN90. Consistent with the substantial exposure ofthe drug and demonstrating target engagement in the brain, the clinical OGA inhibitor ASN90 promoted the O-GlcNAcylation oftau and alpha-synuclein in brains of transgenic mice after daily oral dosing. Across human tauopathy mouse models, oral administrationof ASN90 prevented the development of tau pathology (NFT formation), functional deficits in motor behavior and breathing, andincreased survival. In addition, ASN90 slowed the progression of motor impairment and reduced astrogliosis in a frequently utilized alpha-synuclein-dependent preclinical rodent model of PD. Thesefindings provide a strong rationale for the development of OGAinhibitors as disease-modifying agents in both tauopathies and alpha-synucleinopathies. Since tau and alpha-synuclein pathologies frequentlyco-exist in neurodegenerative diseases, OGA inhibitors represent unique, multimodal drug candidates for further clinicaldevelopment.

Automated summary

Neurodegenerative proteinopathies are characterized by the intracellular formation of insoluble and toxic protein aggregates in the brain that are closely linked to disease progression. In this study, the inhibition of OGA was found to prevent the aggregation and toxicity of tau and alpha-synuclein, suggesting its potential as a therapeutic approach. The novel OGA inhibitor ASN90 demonstrated promising preclinical results, preventing tau pathology, improving motor behavior and survival, and reducing astrogliosis in mouse models.