Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.

Autor:	Himmelbauer MK; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Bajrami B; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Basile R; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Capacci A; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Chen T; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Choi CK; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Gilfillan R; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Gonzalez-Lopez de Turiso F; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Gu C; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Hoemberger M; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Johnson DS; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Jones JH; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Kadakia E; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Kirkland M; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Lin EY; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Liu Y; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Ma B; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Magee T; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Mantena S; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Marx IE; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Metrick CM; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Mingueneau M; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Murugan P; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Muste CA; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Nadella P; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Nevalainen M; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Parker Harp CR; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Pattaropong V; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Pietrasiewicz A; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Prince RJ; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Purgett TJ; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Santoro JC; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Schulz J; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Sciabola S; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Tang H; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Vandeveer HG; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Wang T; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Yousaf Z; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Helal CJ; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States., Hopkins BT; Biogen Research and Development, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 May 23; Vol. 67 (10), pp. 8122-8140. Date of Electronic Publication: 2024 May 07.
DOI:	10.1021/acs.jmedchem.4c00220
Abstrakt:	Multiple 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.
Databáze:	MEDLINE
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