Bruton’s
tyrosine kinase (BTK) is an attractive target in
inflammatory and autoimmune diseases. However, the effectiveness of
BTK inhibitors is limited by side effects and drug resistance. In
this study, we report the development of novel BTK proteolysis targeting
chimeras (PROTACs) with different classes of BTK-targeting ligands
(e.g., spebrutinib) other than ibrutinib. Compound 23 was identified as a potent and fast BTK PROTAC degrader, exhibiting
outstanding degradation potency and efficiency in Mino cells (DC50, 4 h = 1.29 ± 0.3 nM, t1/2, 20 nM = 0.59 ± 0.20 h). Furthermore, compound 23 forms a stable ternary complex, as confirmed by the HTRF
assay. Notably, 23 down-regulated the BTK-PLCγ2-Ca2+-NFATc1 signaling pathway activated by RANKL, thus inhibiting
osteoclastogenesis and attenuating alveolar bone resorption
in a mouse periodontitis model. These findings suggest that compound 23 is a potent and promising candidate for osteoclast-related
inflammatory diseases, expanding the potential of BTK PROTACs.