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.
Authors
- Chaofan Xu
- Mukesh Lulla
- Nupur Bansal (ORCID: https://orcid.org/0000-0003-3226-330X)
- Soumya Negi (ORCID: https://orcid.org/0000-0002-1756-8626)
- Dann Huh
- Thomas M. Carlile (ORCID: https://orcid.org/0000-0002-7699-9354)
- Emily A. Peterson (ORCID: https://orcid.org/0000-0001-5854-2505)
- Guilherme J. Guimaraes (ORCID: https://orcid.org/0000-0001-7778-4905)
- Jessica A. Hurt (ORCID: https://orcid.org/0000-0003-4943-3117)
- Joonsung Lee (ORCID: https://orcid.org/0000-0002-0164-1139)
- James Harvey (ORCID: https://orcid.org/0000-0002-6656-375X)
- Marta Nevalainen
- Philippe N. Bolduc (ORCID: https://orcid.org/0000-0001-8726-4364)
- Andreas Weihofen (ORCID: https://orcid.org/0000-0001-6265-9087)
- Rachelle Driscoll
- Magnus Pfaffenbach (ORCID: https://orcid.org/0000-0002-0068-6829)
- Christina M. Gallo (ORCID: https://orcid.org/0000-0002-6473-9088)
- Patrick Cullen
- David Smith (ORCID: https://orcid.org/0000-0001-9644-2353)
- Neeta A. Abraham
- Catherine L. Guardado
- Thomas J. Purgett
- Yulin Chen (ORCID: https://orcid.org/0000-0001-5679-4055)
- Zain Yousaf
- Kwang Soo Lee
- Joseph C. Santoro
- Sarah Huff
- Eric Stefan
- Zhen Gao
- Melissa M. Kemp
- Colin K. Choi
Institutions
- Translational Genomics Research Institute (US)
- Biogen (United States) (US)
- BioClinica (United States) (US)
- High Throughput Biology (United States) (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-03-17
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c00224
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00