BTK-inhibitor

Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that plays a central role in signal transduction of the B cell antigen receptor and other cell surface receptors in both normal and malignant B lymphocytes. The encoding BTK gene is located on the X chromosome at gene locus Xq22.1. Activation of the Bruton tyrosine kinase (BTK) pathway plays an important role in the pathophysiology of a number of B-cell lymphoproliferative disorders. Several preclinical and clinical studies demonstrated Bruton tyrosine kinase inhibition as a mechanism for the treatment of B-cell lymphoproliferative disorders (Castillo JJ et al. (2016).

A Bruton tyrosine kinase mutant plays a critical role in oncogenic signaling, which is critical for proliferation and survival of leukemic cells in many B-cell malignancies. Originally, BTK was shown to be mutated in the primary antibody deficiency (D80.9) in which all Ig isotypes are reduced with decreased or absent B cells (Bruton`s agammaglobilinemia, also called XLA =X-linked agammaglobulinemia).

Previously approved BTK inhibitors:

• Ibrutinib
• acalabrutinib and
• Zanubrutinib

BTK inhibitors (BTKis) have increasingly replaced chemotherapy for various malignant lymphomas in recent years (Liu J et al 2021). Bruton tyrosine kinase inhibitors are most effective in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but have also been approved for Waldenström macroglobulinemia, small lymphocytic lymphoma (SLL), marginal zone lymphoma, and chronic graft-versus-host disease (Brullo C et al. (2021).

The first-generation inhibitor, ibrutinib, acts by covalently irreversibly binding to BTK (irreversible BTK inhibitor), a non-receptor tyrosine kinase of the TEC (transient erythroblastopenia of childhood) family that plays a critical role in B-cell receptor signaling (Sibaud V et al 2020). Ibrutinib also causes "off-target" inhibition of other kinases, such as epidermal growth factor receptor (EGFR), Src tyrosine kinases (Src= compound acronym of cellular and sarcoma) and other kinases of the TEC family (interleukin-2-inducible T-cell kinase also referred to as ITK as well as BMX).

Subsequently, second-generation BTKis have been developed that differ from ibrutinib, as an irreversible BTK inhibitor, by their specificity for BTK (reversible BTK inhibitors). They therefore stand out from ibrutinib in terms of side effects or efficacy (Liang C et al 2018). An example of this is acalabrutinib.

BTKi exhibit a number of drug-food interactions that can alter drug efficacy and/or increase toxicity (Fancher KMet al.2020). For example, zanubrutinib in humans is metabolized primarily by CYP3A. It can be assumed that with other BTKis, an influence on the active levels can also be expected with appropriate co-medication (Mu S et al. 2020).

Current clinical practice is the continuous long-term administration of BTKi, which can be complicated by adverse effects or the development of drug resistance. Alternatives to the long-term use of BTKi are currently being developed, such as combination therapies that allow for time-limited therapy.

The 2nd generation BTK inhibitors acalabrutinib and zanubrutinib, were developed to optimize BTK inhibition and minimize off-target inhibition of alternative kinases (Tec, ITK, EGFR, SRC kinases). These drugs were recently approved by the FDA for relapsed or refractory mantle cell lymphoma.

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