Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Abstract

The cytoplasmic protein-tyrosine kinase BTK plays an essential role for differentiation and survival of B-lineage cells and, hence, represents a suitable drug target. The number of BTK inhibitors (BTKis) in the clinic has increased considerably and currently amounts to at least 22. First-in-class was ibrutinib, an irreversible binder forming a covalent bond to a cysteine in the catalytic region of the kinase, for which we have identified 228 active trials listed at ClinicalTrials.gov. Next-generation inhibitors, acalabrutinib and zanubrutinib, are approved both in the United States and in Europe, and zanubrutinib also in China, while tirabrutinib is currently only registered in Japan. In most cases, these compounds have been used for the treatment of B-lymphocyte tumors. However, an increasing number of trials instead addresses autoimmunity and inflammation in multiple sclerosis, rheumatoid arthritis, pemphigus and systemic lupus erythematosus with the use of either irreversibly binding inhibitors, e.g., evobrutinib and tolebrutinib, or reversibly binding inhibitors, like fenebrutinib. Adverse effects (AEs) have predominantly implicated inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain. Analysis of the reported AEs suggests that ibrutinib-associated atrial fibrillation is caused by binding to ERBB2/HER2 and ERBB4/HER4. However, the binding pattern of BTKis to various additional kinases does not correlate with the common assumption that skin manifestations and diarrhoeas are off-target effects related to EGF receptor inhibition. Moreover, dermatological toxicities, diarrhoea, bleedings and invasive fungal infections often develop early after BTKi treatment initiation and subsequently subside. Conversely, cardiovascular AEs, like hypertension and various forms of heart disease, often persist.

Keywords: X-linked agammaglobulinemia; acalabrutinib; atrial fibrillation; diarrhoea; ibrutinib; infection; rash; zanubrutinib.

FIGURE 1

Effects of FDA-approved BTK-inhibitors targeting tyrosine kinases with conserved cysteine. Inhibition of the kinases is depicted with and corresponding to strong and weak inhibition, respectively. ** Major bleedings are more frequent upon ibrutinib treatment versus more selective BTKi. *The association between the kinase inhibition and the side effect is not entirely obvious, since the observed adverse event occurs even if the kinase is not inhibited. EGFR is expressed in the epithelial cells in the gut and skin, but we do not favour a direct association between EGFR-inhibition and diarrhoea/rash. The same is the case for TEC, which is expressed in cardiomyocytes and thrombocytes and not inhibited by acalabrutinib, while the corresponding side effects still occur. HER2 and HER4 are in dashed box, since we favour the association of the simultaneous inhibition of these two kinases with atrial fibrillation. (n.i.) no inhibition. Cardiomyocyte and epithelial cells were created with BioRender.com.