Bruton tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in carcinogenic signaling. Meanwhile, it plays a central role in the signal transduction of B cell antigen receptors and other cell surface receptors in normal and malignant B lymphocytes. Carcinogenic signaling is crucial for the proliferation and survival of leukemia cells in many B-cell malignancies. Nonetheless, BTK plays multiple roles in monocytes of the innate immune system, especially in dendritic cells and macrophages. In addition, BTK plays a role in several bone marrow cell populations that represent an important part of the tumor microenvironment.

Besides, BTK is also relevant to many other signaling pathways in B cells, including chemokine receptors, Toll-like receptors (TLRs), and Fc receptor signaling pathways. Moreover, BTK has also been identified as a direct regulator of NLRP3 inflammasome, a key innate inflammatory mechanism. Therefore, people are very interested in BTK inhibition as an anticancer therapy, not only in B-cell malignant tumors but also in solid tumors. Furthermore, BTK inhibition is a promising treatment method for various blood cancers and autoimmune diseases. Here, we will introduce an orally active, highly selective BTK inhibitor, BGB-8035.

BGB-8035 is an Orally Active BTK Inhibitor for B-cell Malignancies and Immunology Research.

At first, BGB-8035 is a BTK inhibitor with IC50s of 1.1 nM, 99 nM, and 621 nM for BTK, TEC, and EGFR, respectively. Particularly, BGB-8035 has antitumor and anti-arthritis activity. Obviously, BGB-8035 has the potential for B-cell malignancies and autoimmune disease research.

Secondly, BGB-8035 is nontoxic HEK293 and Ramos cells (IC50>10 μM, both). Specifically, BGB-8035 with 7.5, 15, 30 mg/kg by PO twice daily for 16 days demonstrates dose-dependent antitumor activity.
Thirdly, BGB-8035 inhibits arthritis as measured by clinical scores in a dose-dependent manner in the Lewis rats aged 8-9 weeks with CIA model. Interestingly, BGB-8035 prevents the CIA model-associated body weight loss.

Finally, BGB-8035 is an orally active, highly selective BTK inhibitor.


Yunhang Guo, et al. J Med Chem. 2023 Mar 23;66(6):4025-4044.