B cells, T cells, and natural killer cells are essential lymphocytes in our immune system. Like all cells, they contain enzymes, or kinases, that play a key role in regulating cell function and proliferation. Lymphocytes depend on Tec family kinases. These include Bruton's tyrosine kinase, or BTK, in B cells; Tec, ITK, and TXK in T cells; and ITK in natural killer cells.1


BCR, B-cell receptor; BLNK, B-cell linker; BTK, Bruton's tyrosine kinase; CD, cluster of differentiation; IKK, I kappa B kinase; PLCg2, phospholipase Cg2; LYN, Lck/Yes novel tyrosine kinase; mTOR, mammalian target of rapamycin; NF-kB, nuclear factor kappa-light chain enhancer of activated B-cells; NFAT, nuclear factor of activated T-cells; PKC, protein kinase C; PLC, phospholipase C; SYK, spleen tyrosine kinase

BTK plays a key role in the B-cell receptor, or BCR, pathway which regulates the development, function, and survival of the B cell.2 BTK has been implicated in the pathogenesis of B cell malignancies—including chronic lymphocytic leukemia, or CLL—and has recently emerged as an important therapeutic target.3 In a malignant or cancerous B cell, BTK may become overexpressed and persistently activated, allowing the cell to thrive in the peripheral blood, bone marrow, and lymph nodes.

Inhibiting BTK is a promising approach to managing CLL.4 The hypothesized mechanism of action—based on preclinical experiments—is that inhibiting BTK reduces vital growth and survival signaling to malignant B cells. This, in turn, may also prevent the malignant CLL cells from anchoring and proliferating within the nurturing tumor microenvironment5 and reduce necessary prosurvival signaling and crosstalk with other immune cells.6

BTK plays a key role in the B-cell receptor, or BCR, pathway which regulates the development, function, and survival of the B cell.

In preclinical studies, inhibiting BTK has also been shown to interfere with the ability of malignant B cells to recognize chemical signals that would guide them to the nurturing microenvironment. This may lead to transient lymphocytosis—a redistribution of CLL cells from the bone marrow and lymph nodes into the peripheral blood.5 Outside of the nurturing microenvironment, the malignant B cells may struggle to survive.

Acerta Pharma has applied its expertise in covalent technology to the selective targeting of BTK while minimizing inhibition of non-BTK kinases. Its BTK inhibitor, ACP-196, also known as acalabrutinib, is currently in clinical development. Acalabrutinib is a small-molecule oral drug candidate that covalently binds to BTK. It was designed to be highly selective and potent in inhibiting BTK while preclinical experiments suggest that acalabrutinib may have minimal impact on other kinases like Tec, ITK, TXK, and EGFR.7

Acalabrutinib has now been approved by the FDA for adults with mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer. Acalabrutinib is still undergoing clinical trials in other hematological disease areas. For a list of available trials, visit www.clinicaltrials.gov.

1 Berg et al. Ann Rev Immunol. 2005.
2 Küppers et al. Nat Rev Cancer. 2005.
3 Akinleye et al. J Hematol Oncol. 2013.
4 Wiestner. Hematology Am Soc Hematol Educ Program. 2014.
5 Ten Hacken and Burger. Pharmacol Ther. 2014.
6 Niemann et al. AACR. 2014. Abstr 2624.
7 Covey et al. AACR. 2015. Abstr 2596.