New Insights on Bruton’s Tyrosine Kinase Inhibitors

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Background

Pharmaceutical inhibitors of BTK (Bruton’s Tyrosine Kinase) are breakthrough medicines for various forms of leukemia and lymphoma. Many new compounds are under development and the field is rapidly expanding. While treatment for tumors has paved the way for the development of blockers, other indications, such as autoimmunity, are expected to become major future indications. BTK is an intracellular enzyme found in hematopoietic cells. When defective, it manifests itself as a primary immunodeficiency, which owing to the location of the BTK gene on the X-chromosome, essentially only affects boys. These patients lack mature B-lymphocytes, cannot mount adequate antibody responses, and hence become susceptible to infections. The first member of this new class of compounds, ibrutinib (Imbruvica®) has been FDA approved for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, Waldenström’s macroglobulinemia, marginal zone lymphoma, and graft-versus-host disease. Worldwide more than 20 inhibitors are under development. Apart from ibrutinib, acalabrutinib and zanubrutinib are both now FDA approved, and evobrutinib has reached far in clinical development. These four inhibitors all bind irreversibly to cysteine 481 in the kinase domain. Reversibly interacting, non-covalent binding blockers, which have a different mode of binding to the catalytic region, have also been developed.

Over time a large percentage of patients treated with irreversibly binding inhibitors no longer respond. Resistance is mainly caused by mutations affecting either BTK, preventing the covalent binding to C481, or in BTK’s substrate, phospholipase C 2 (PLCG2). The mutations in the PLCG2 gene cause the enzyme to become constitutively active. Even if the non-covalent inhibitors have not yet been extensively studied, there are indications that patients with resistance to covalent blockers will still be sensitive to reversible inhibitors. Clinical trials of non-covalent inhibitors are ongoing in patients with resistance to covalent blockers.

The various inhibitors differ in their specificity. Ibrutinib is known to bind irreversibly also to some other enzymes carrying the corresponding cysteine, and to interact non-covalently with another set of kinases, too. The interaction profiles of acalabrutinib, evobrutinib and zanubrutinib are more restricted, with the goal of reducing side effects. The inhibition of other kinases seems to be the underlying mechanism for many of the side effects. BTK inhibitors have been combined with other drugs, and recently it was reported that the combination of ibrutinib and a BCL-2 blocker resulted in very deep remissions in CLL.

This Research Topic covers various aspects of BTK inhibitors. We welcome the submission of hypothesis and treatment recommendations, as well as a limited number of mini-reviews focusing on, but not limited to, the following subtopics:

1. Novel inhibitors and their biological activity, including off-target effects in immune cells.
2. Structure-function relationships related to small-molecule binding to BTK/TEC-family members
3. Drug resistance and underlying mechanisms, including genetic aspects
4. Observations in leukemia and lymphoma patients treated with BTK inhibitors
5. Observations in patients treated for non-malignant disease with BTK inhibitors such as autoimmune diseases

Keywords: BTK, kinase, BTK inhibitor, ibrutinib, leukemia, lymphoma, autoimmunity, drug resistance

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