In this article, we will introduce a selective, reversible, and orally active BTK inhibitor, BIIB068. As a selective inhibitor, BIIB068 exhibits an IC50 of 1 nM and a Kd of 0.3 nM against BTK. It shows more >400-fold selective for BTK than other kinases.

BIIB068 improves the whole blood cell potency with an IC50 of 0.12 µM. It also inhibits BCR mediated PLCγ2 phosphorylation in Ramos B cells, exhibiting an IC50 of 0.4 µM. Additionally, in human PBMCs, BIIB068 inhibits anti-IgD induced and anti-IgM BCR-induced B cell activation with IC50 values of 0.11 µM and 0.21 µM, respectively. In neutrophils, BIIB068 inhibits FcγR-mediated ROS production with an IC50 of 54 nM.

In animal PK study, BIIB068 is stable in the plasma of mouse, rat, beagle dog, and cynomolgus monkey.

After 6 hours’ BIIB068 intravenous injection, >95% parent compound remaining in plasma. Besides, BIIB068 exhibits good drug-like properties in rats. BIIB068 results in low in vivo clearance (CL %Qh = 6) and moderate oral bioavailability (%F = 48). After oral administration at 5 mg/kg, BIIB068 shows the T1/2 of 1.2 hours, 2.1 hours, and 0.9 hours for rats, dog, and cynomolgus monkey, respectively.

In order to evaluate the effects of BIIB068 on BTK-dependent B cell activation in vivo, the antigen-specific antibody response is measured from mice by BIIB068 orally administration for 10 consecutive days.
BIIB068 administration twice daily results in substantial reductions of these antibody titers in animals. When it compares to the control group, BIIB068 reduces the anti SNP IgM antibody titers 93%, 90%, 63%, 22% and -23% at the dose of 50, 30, 10, 3 and 1 mg/kg/dose, respectively. Whatmore, the IgM antibody titer ED50 value is 4.4 mg/kg/dose after BIIB068 administration in the TI-2 efficacy model.

In conclusion, BIIB068 is a potent  BTK inhibitor with favorable preclinical toxicology and DMPK properties across species. It represents a reversible BTK inhibitor for the research of autoimmune diseases.


Bin Ma, Tonika Bohnert, et al. J Med Chem. 2020 Jul 22.