Brain penetrant small molecules drugs that target tau pre-mRNA and modulate 3R to 4R tau splicing

Rationale:

Small molecules that target tau pre-mRNA and are able to increase 3R, while decreasing 4R Tau splice forms in the brain have great potential as disease modifying drugs for primary tauopathies that associated with 4R tau pathology.

Drug Discovery Program Status:

This fully integrated small molecule drug discovery program with team support at Charles River Labs used structure-based and computed-aided drug design and ADME supported medicinal chemistry to generate brain penetrant small molecules. PK/PD correlation will stablish target engagement and support in vivo efficacy studies in models of tauopathies. The program is currently in late stage hit to lead.

Executive Summary:

The MAPT gene encodes the microtubule-associated protein tau (MAPT) whose transcript undergoes complex regulated alternative splicing, giving rise to several mRNA species. MAPT transcripts are differentially expressed in the nervous system depending on stage of neuronal maturation and neuron type. MAPT gene mutations have been associated with several neurodegenerative disorders such as Alzheimer’s disease, frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy.
Small molecules that target tau pre-mRNA and are able to increase 3R, while decreasing 4R Tau splice forms in the brain have great potential as disease modifying drugs for primary tauopathies that associated with 4Rtau pathology.