A Fast and Clean BTK Inhibitor

Abstract

Bruton's tyrosine kinase (BTK) is a major drug target for B-cell related malignancies; however, existing BTK inhibitors approved for cancer treatment have significant off-targets that limit their use for autoimmune and inflammatory diseases. Remibrutinib (LOU064) is a novel covalent BTK inhibitor that binds an inactive BTK conformation, which affords it unprecedented selectivity. Its optimization led to rapid BTK engagement in vivo and fast clearance, further limiting systemic exposure. Remibrutinib is currently in phase 2 clinical trials for treatment of chronic urticaria and Sjoegren's syndrome.

Figure 1

Remibrutinib achieves selectivity by binding an inactive conformation of BTK. (A) Structure of BTK-remibrutinib complex (PDB code 6TFP). In the complex Tyr551 (white) is rotated inward and interacts with the cyclopropylphenyl group and is unavailable for phosphorylation. The active conformation of Tyr551 in the complex of BTK with ibrutinib is depicted in green (PDB code 5P9J). (B) Relative binding of ibrutinib and remibrutinib to various kinases, illustrating the dramatic differences in selectivity.

Figure 2

Rapid binding and fast clearance limit systemic exposure. Shown is a schematic illustration of remibrutinib binding and clearance dynamics. Rapid, irreversible binding to BTK, coupled with fast clearance, enables achievement of high BTK occupancy for extended periods of time with a transient dose of the inhibitor.