Elsubrutinib (ABBV-105) is a highly active, potent, and selective orally-administered inhibitor of Bruton's tyrosine kinase (BTK). It irreversibly inhibits the catalytic domain of BTK with an IC50 value of 0.18 μM. Elsubrutinib holds potential for the advancement of research on inflammatory diseases.

BTK:0.18 μM (IC50)

Elsubrutinib is a chemical compound that selectively targets and irreversibly inhibits the activity of Bruton's tyrosine kinase (BTK), notably demonstrating a marked decrease in effectiveness (IC 50 of 2.6 μM) against the BTK (C481S) mutation, underscoring the critical role of Cys481 in its mechanism of action. This inhibition disrupts BTK-dependent cellular activation. Additionally, Elsubrutinib effectively reduces histamine and IL-6 release from IgE-stimulated basophils and IgG-stimulated monocytes, respectively, and inhibits IgM-mediated B cell proliferation, which is dependent on BCR signaling. Furthermore, it suppresses TNF release from CpG-DNA stimulated peripheral blood mononuclear cells (PBMCs) through TLR9 signaling, without affecting TLR functions that do not involve ITAM motifs. This highlights Elsubrutinib's significant influence on immune response modulation, particularly in IgM-mediated B cell proliferation.

Elsubrutinib, administered orally (p.o.) at a dosage of 10 mg/kg, selectively inhibits antibody responses to antigens NP-Ficoll and NP-KLH without affecting responses to NP-LPS or Prevnar-13. It also demonstrates a dose-dependent inhibition of paw swelling in disease models and significantly mitigates the onset of proteinuria and enhances survival at doses of 10 mg/kg, both once daily (QD) and twice daily (BID). Lower doses fail to significantly impact these endpoints. Additionally, Elsubrutinib shows an exposure-dependent reduction in paw volume increases and significantly reduces bone volume loss in a manner aligned with its anti-inflammatory properties. These effects were observed across different animal models, including female C57/BL6 mice for antibody response inhibition, Lewis rats for paw swelling inhibition, and NZBWF1 mice for proteinuria and survival outcomes, signifying its potential in therapeutic applications.