Discovery and Optimization of Thienopyrazine RNA-Splicing Modulators for the Treatment of Huntington’s Disease

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG-repeat expansion in the Huntington gene (HTT). Herein, we describe the discovery of a series of HTT pre-mRNA-splicing modulators that promote the inclusion of a cryptic stop codon that in turn lowers levels of mutant Huntington protein (mHTT). Optimization of the starting thienopyridine amide core resulted in the discovery of the potent, CNS-penetrant, selective, and orally bioavailable HTT-splicing modulator BIO-6553. This lead compound is structurally distinct from existing splicing modulators, demonstrated significant HTT-lowering in both human cells and mouse YAC128 models, and has an attractive off-target profile from RASL- and RNA-seq analysis.