Bruton's Tyrosine Kinase Inhibitors (BTKIs): Review of Preclinical Studies and Evaluation of Clinical Trials

Abstract

In the last few decades, there has been a growing interest in Bruton's tyrosine kinase (BTK) and the compounds that target it. BTK is a downstream mediator of the B-cell receptor (BCR) signaling pathway and affects B-cell proliferation and differentiation. Evidence demonstrating the expression of BTK on the majority of hematological cells has led to the hypothesis that BTK inhibitors (BTKIs) such as ibrutinib can be an effective treatment for leukemias and lymphomas. However, a growing body of experimental and clinical data has demonstrated the significance of BTK, not just in B-cell malignancies, but also in solid tumors, such as breast, ovarian, colorectal, and prostate cancers. In addition, enhanced BTK activity is correlated with autoimmune disease. This gave rise to the hypothesis that BTK inhibitors can be beneficial in the therapy of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjögren's syndrome (SS), allergies, and asthma. In this review article, we summarize the most recent findings regarding this kinase as well as the most advanced BTK inhibitors that have been developed to date and their clinical applications mainly in cancer and chronic inflammatory disease patients.

Keywords: Bruton’s tyrosine kinase; Bruton’s tyrosine kinase inhibitors; autoimmune disease; cancer; solid tumor.

Figure 1

Schematic representation of the BTK structure. (A) PH—the pleckstrin homology domain, which has the capacity to bind phospholipids, allowing BTK to be recruited from the cytosol to the plasma membrane. TH—the Tec homology domain, which is required for the stability of BTK. SH3, SH2—Src domains are important in protein–-protein interactions. SH2 is a phosphoamino acid binding domain that specifically recognizes phosphotyrosine residues. Kinase domain—the protein’s catalytic domain [7]; BTK activation in the B-cell receptor (BCR) pathway. When the SH3 domain of BTK binds to the SH2-kinase linker, it locks the kinase domain into an inactive conformation, resulting in a compact and autoinhibited Src-like module of BTK. Both the assembled conformation of the Src-like module of BTK and the inactive conformation of the kinase domain are stabilized by the PH-TH module. In the next step, the PH-TH module binds to two PIP3 lipids, which triggers the dimerization of the BTK PH-TH module on the membrane in a switch-like manner. This in turn activates BTK by trans-autophosphorylation [8,9] (B).

Figure 2

Structures of BTK isoforms. pY223 and pY551 are activating phosphorylation sites; C481 is a binding site for BTK inhibitors ibrutinib, spebrutinib, and acalabrutinib [10]. In this review, the term “BTK” refers to the BTK-A isoform unless it is clearly stated otherwise.

Figure 3

BTK pathway. BCL10—B-cell lymphoma/leukemia 10 protein, BCR—B cell receptor, CAM—calmodulin, CARD11—caspase recruitment domain-containing protein 11, CN—calcineurin, CXCR4—chemokine receptor type 4, DAG—diacylglycerol, ERK1/2—extracellular signal-regulated protein kinase ½, IKK—inhibitor of NF-κB kinase, IP3—inositol 1,4,5-trisphosphate, MALT1—mucosa-associated lymphoid tissue lymphoma translocation protein 1, MAPK—mitogen-activated protein kinase, MEK1/2—MAPK/ERK kinase ½, MYC—transcription factor, MYD88—myeloid differentiation primary response protein 88, NFAT—nuclear factor of activated T-cells, NF-кB—nuclear factor kappa-light-chain-enhancer of activated B-cells, PKCβ—protein kinase C β, PLCγ2—phospholipase Cγ2, RAS—rat sarcoma virus GTPase, SRC—protooncogene tyrosine-protein kinase, TLR—toll-like receptor.

Figure 4

BTKIs approved by the FDA [67,68,69].