2. Academic Validation
  3. Leveraging Kinase Drugs for Neurosciences: Discovery of Selective, CNS-Penetrant Reversible Bruton's Tyrosine Kinase Inhibitors as Therapeutics for Neuroinflammation

Leveraging Kinase Drugs for Neurosciences: Discovery of Selective, CNS-Penetrant Reversible Bruton's Tyrosine Kinase Inhibitors as Therapeutics for Neuroinflammation

  • J Med Chem. 2026 Apr 23;69(8):8818-8837. doi: 10.1021/acs.jmedchem.5c02648.
Brian T Hopkins 1 2,  Isaac E Marx 1,  Harlod George Vandeveer 1,  Marta Nevalainen 1,  Rebecca Basile 3,  Bekim Bajrami 4,  Colin K Choi 5,  Richard J Grater 6,  Chungang Gu 6,  Marc Hoemberger 7,  Ekta Kadakia 6,  Sudarshan K Kapadnis 6,  Ying Liu 6,  Bin Ma 1,  Tom Magee 5,  Claire M Metrick 8,  Michael Mingueneau 3,  Cathy A Muste 3,  Chelsea R Parker Harp 3,  Robin J Prince 1,  Joseph C Santoro 7,  Jurgen Schulz 1,  Simone Sciabola 1,  Hao Tang 3,  Ti Wang 7,  Robert Meissner 1,  Tonika Bohnert 6
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Biogen Inc, Biotherapeutics and Medicinal Sciences, Cambridge, Massachusetts 02142, United States.
  • 2 Pharmaceutical Operations and Technology, Biogen Inc, Biotherapeutics and Medicinal Sciences, Cambridge, Massachusetts 02142, United States.
  • 3 Neuroinflammation Research, Biogen Inc, Biotherapeutics and Medicinal Sciences, Cambridge, Massachusetts 02142, United States.
  • 4 Chemo-Proteomics, Biogen Inc, Biotherapeutics and Medicinal Sciences, Cambridge, Massachusetts 02142, United States.
  • 5 Non-Clinical Safety, Biogen Inc, Biotherapeutics and Medicinal Sciences, Cambridge, Massachusetts 02142, United States.
  • 6 DMPK, Biogen Inc, Biotherapeutics and Medicinal Sciences, Cambridge, Massachusetts 02142, United States.
  • 7 Bio-Assays, Biogen Inc, Biotherapeutics and Medicinal Sciences, Cambridge, Massachusetts 02142, United States.
  • 8 Structural Biology, Biogen Inc, Biotherapeutics and Medicinal Sciences, Cambridge, Massachusetts 02142, United States.
PMID: 41944394 DOI: 10.1021/acs.jmedchem.5c02648
Abstract

Bruton's tyrosine kinase (Btk) is a nonreceptor tyrosine kinase clinically validated to impact B-cell development. Molecules designed to target Btk, through either covalent or reversible inhibition, have transformed the treatment of hematopoietic malignancies. Wen, T.; Wang, J.; Shi, Y.; Qian, H.; Liu, P. Inhibitors targeting Bruton's tyrosine kinase in cancers: drug development advances. Leukemia 2021, 35(2), 312-332.10.1038/s41375-020-01072-6. These advancements are paving the way for new therapeutics to treat nononcology indications, De Bondt, M.; Renders, J.; Struyf, S.; Hellings, N. Inhibitors of Bruton's tyrosine kinase as emerging therapeutic strategy in autoimmune diseases. Autoimmun. Rev. 2024, 23(5), 103532.10.1016/j.autrev.2024.103532 such as multiple sclerosis (MS), and provide benefits to patients with progressive disease. In this context, we describe the discovery of a highly selective, CNS-penetrant, reversible Btk Inhibitor designed to sequester Tyr-551, the critical phosphorylation site, into an inactive conformation, thereby blocking B-cell receptor (BCR) signaling. While this class of molecules demonstrated excellent safety when administered at doses that fully inhibited B-cell activity in the periphery, increasing exposure to achieve similar efficacy in the CNS led to adverse findings. This raises the question of whether it was a molecule-specific off-target toxicity or a consequence of blocking Btk function in microglia.

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