Martin K. Himmelbauer, Bekim Bajrami, Rebecca Basile, Andrew Capacci, TeYu Chen, Colin K. Choi, Rab Gilfillan, Felix Gonzalez-Lopez de Turiso, Chungang Gu, Marc Hoemberger, Douglas S. Johnson, J. Howard Jones, Ekta Kadakia, Melissa Kirkland, Edward Y. Lin, Ying Liu, Bin Ma, Tom Magee, Srinivasa Mantena, Isaac E. Marx, Claire M. Metrick, Michael Mingueneau, Paramasivam Murugan, Cathy A. Muste, Prasad Nadella, Marta Nevalainen, Chelsea R. Parker Harp, Vatee Pattaropong, Alicia Pietrasiewicz, Robin J. Prince, Thomas J. Purgett, Joseph C. Santoro, Jurgen Schulz, Simone Sciabola, Hao Tang, H. George Vandeveer, Ti Wang, Zain Yousaf, Christopher J. Helal, and Brian T. Hopkins
Journal of Medicinal Chemistry 2024
DOI: 10.1021/acs.jmedchem.4c00220Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton’s tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (25), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 (25) demonstrated efficacy in disease-relevant preclinical in vivo models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.
