BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

Abstract

Bruton's tyrosine kinase (BTK) is an essential component of multiple signaling pathways that regulate B cell and myeloid cell proliferation, survival, and functions, making it a promising therapeutic target for various B cell malignancies and inflammatory diseases. Five small molecule inhibitors have shown remarkable efficacy and have been approved to treat different types of hematological cancers, including ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib. The first-in-class agent, ibrutinib, has created a new era of chemotherapy-free treatment of B cell malignancies. Ibrutinib is so popular and became the fourth top-selling cancer drug worldwide in 2021. To reduce the off-target effects and overcome the acquired resistance of ibrutinib, significant efforts have been made in developing highly selective second- and third-generation BTK inhibitors and various combination approaches. Over the past few years, BTK inhibitors have also been repurposed for the treatment of inflammatory diseases. Promising data have been obtained from preclinical and early-phase clinical studies. In this review, we summarized current progress in applying BTK inhibitors in the treatment of hematological malignancies and inflammatory disorders, highlighting available results from clinical studies.

Keywords: BTK; Clinical trials; Hematological malignancies; Inflammatory diseases; Inhibitors; Signaling pathways.

Fig. 1

Key milestones in the development of BTK inhibitors, with approved indications. XLA X-linked agammaglobulinemia; GVHD graft-versus-host disease; R/R relapsed and refractory; TN treatment-naïve

Fig. 2

BTK’s structure and interactions. BTK contains 659 amino acids and five domains from the N-terminus to the C-terminus, including an amino-terminal pleckstrin homology domain (PH domain), a proline-rich TEC homology (TH) domain, the SRC homology domains SH2 and SH3 domains, and a catalytic domain. Phosphorylation of the Y551 and Y223 sites is necessary for the activation of BTK. Cys481 residues on the catalytic domain are the main targets for the approved BTK inhibitors

Fig. 3

Role of BTK in BCR signaling, TLR signaling, chemokine receptor signaling, and FcR signaling pathways. Upon antigen binding, BCR signaling is activated involving the formation of a “micro-signalosomes” composed of PI3K, BTK, BLNK, and PLCγ2. Activated BTK leads to the phosphorylation of PLCγ2 and stimulates its lipase activity, resulting in Ca²⁺ influx and the activation of the NFAT transcription factors via calmodulin (CaM). Activation of PLCγ2 also induces the activation of PKCβ via DAG, which subsequently activated the ERK1/2 and NF-κB signaling pathways. Activation of BCR signaling can promote B cell proliferation, survival, and functions. In addition, activation of TLR and chemokine receptors can activate BTK and regulate the adhesion, migration, and production of pro-inflammatory cytokines in B cells and myeloid cells. BTK-dependent FcR signaling is essential for histamine release from mast cells, enhanced antigen presentation and cytokine generation from myeloid cells, and controls osteoclast differentiation and osteoclastogenesis. SHIP1 and SHP1 are negative regulators of BTK’s activity

Fig. 4

Chemical structures of the approved BTK inhibitors