RÉSUMÉ
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.
Sujet(s)
Agammaglobulinaemia tyrosine kinase , Encéphale , Sclérose en plaques , Inhibiteurs de protéines kinases , Agammaglobulinaemia tyrosine kinase/antagonistes et inhibiteurs , Agammaglobulinaemia tyrosine kinase/métabolisme , Sclérose en plaques/traitement médicamenteux , Humains , Animaux , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/pharmacocinétique , Inhibiteurs de protéines kinases/composition chimique , Encéphale/métabolisme , Souris , Découverte de médicament , Encéphalomyélite auto-immune expérimentale/traitement médicamenteux , Rats , Relation structure-activité , Prolifération cellulaire/effets des médicaments et des substances chimiques , FemelleRÉSUMÉ
Dendrimers with molecular weights ranging from ca. 2700 to 11 000 and from 16 to 64 homoallyl ether end groups were cross-linked using the Grubbs ring-closing metathesis reaction. A combination of SEC, MALDI-TOF-MS, and AFM were used to characterize the cross-linked nanoparticles. The data suggest a significant decrease in volume with cross-linking and a concomitant increase in rigidity, both of which can be controlled independently with a fair degree of precision.