Bruton's Tyrosine Kinase (BTK) Inhibitor Program

BTK is an important cell signaling enzyme that is found in hematopoietic (blood) cells including B-cells. B-cell activation is driven by the B-cell receptor (BCR), and BTK is a crucial part of the BCR signaling pathway.

BCR signaling is thought to promote cell proliferation, adhesion, and survival in many types of B-cell malignancies (cancers). Inhibitors of BTK such as the Pharmacyclics compound PCI-32765, act downstream of the BCR and block BTK activity, and in preclinical models this resulted in an inhibition of proliferation, a disruption of tumor cell adhesion, and apoptosis (cell death) in malignant B-cells. Inhibition of BTK also blocked the recruitment and function of other immune cells including monocytes, macrophages, and mast cells. Studies in mice have shown that orally-dosed PCI-32765 reduces the level of circulating autoantibodies and can reverse the course of arthritis. PCI-32765 also inhibited auto-antibody production and the development of kidney disease in a mouse model of systemic lupus erythematosus (SLE).

Therefore, targeted inhibition of BTK is a novel approach for treating many different human diseases associated with the inappropriate activation of B-cells, including B-cell malignancies, and potentially autoimmune and inflammatory disorders.

Pharmacyclics' BTK Inhibitor PCI-32765 is an investigational, orally active, selective and irreversible small molecule that is in clinical development in a variety of B-cell malignancies (including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (cancer of plasma cells, a type of white blood cell present in bone marrow).