With millions of new deaths every year, cancer is one of the leading causes of mortality worldwide, with over 19.9 million deaths in 2020 [1]. Despite substantial advancements in cancer research, the quest for a definitive treatment approach remains elusive. Consequently, a diverse array of treatment methods has been developed to improve patient outcomes. Mainly these methods include chemotherapy, immunotherapy, radiotherapy, targeted therapy, hormone therapy, stem cell transplantation, and surgical interventions, each tailored to specific cancer types and stages [1]. Moreover, researchers are diligently working on developing protective vaccines against certain cancer types, providing a proactive approach to cancer prevention and treatment. However, the complex and multifactorial nature of cancer demands a deeper understanding of the underlying molecular mechanisms that drive its initiation, progression, and resistance to therapies.

The development and progression of cancer are complex processes involving intricate signaling pathways and the interaction of messenger molecules within the cell nucleus. Disruptions in these signaling pathways can lead to a cascade of events, including abnormal gene overexpression, irregular protein clustering, dysregulated protein family production, and other contributing factors that drive cancer progression. Understanding these underlying mechanisms is critical for the development of targeted therapies that can effectively inhibit cancer growth and improve patient outcomes.

In the intricate landscape of cancer development, an essential group of proteins known as the Bruton Tyrosine Kinases (BTKs) hold significant importance within the academy and pharmaceutical industry. Found predominantly in the cytoplasm of B lymphocytes, BTKs play a pivotal role in signal transduction for B cell receptors, orchestrating vital cellular processes such as B cell signaling, mast cell activation, and neutrophil migration to inflamed regions of the body. These kinases comprise five distinct subdomains: the amino-terminal plextrin homology (PH) domain, a proline-rich TEC homology (TH) domain, a kinase domain with enzymatic activity, and SRC homology (SH) domains SH2 and SH3 [[1], [2], [3], [4]]. This unique domain architecture empowers BTKs to execute crucial functions in cellular signaling and immune responses.

The clinical significance of BTKs is evident from their indispensable role in human B cell ontogenesis. Mutations in the BTK gene lead to X chromosome-linked agammaglobulinemia (XLA), a severe immunodeficiency disorder that ultimately progresses to chronic lymphocytic leukemia (CLL) [[2], [3], [4]]. Beyond cancer, BTKs play a critical role in numerous other diseases, positioning them as attractive therapeutic targets for a wide range of conditions. They play a pivotal role in signal transduction for B cell receptors and are involved in vital cellular processes, including B cell signaling, mast cell activation, and neutrophil migration to inflamed body regions. The dysregulation of BTK signaling has been implicated in the pathophysiology of numerous autoimmune and inflammatory diseases, underscoring BTKs' potential as therapeutic targets for B cell malignancies [[5], [6], [7]]. The intricate expression patterns of BTK in different hematopoietic cells significantly influence the development of effective BTK-targeted therapeutics. Notably, B cells and myeloid cells exhibit more robust expression of BTK [8]. Throughout B cell development, BTK expression is dynamically regulated, reaching its peak in mature B cells. This has important implications, as increased BTK expression has been identified in various B cell malignancies, including mantle cell lymphoma and CLL [9]. To design effective BTK-targeted therapies, a comprehensive understanding of BTK expression patterns in both healthy and malignant cells is indispensable.

The BTK family of non-receptor tyrosine kinases exhibit a specific domain organization, which contributes to their functional diversity and ability to interact with various signaling partners. The PH domain of BTK is responsible for binding to phosphoinositides, particularly phosphatidylinositol-3,4,5-trisphosphate (PIP3), which is generated by the plasma membrane-associated lipid kinase phosphatidylinositol-3-kinase (PI3K). The kinase domain of BTK, with its enzymatic activity, is a central player in the signal transduction process. Upon recruitment to the plasma membrane and activation, BTK undergoes autophosphorylation, leading to its full activation. The SH2 and SH3 domains of BTK are involved in mediating protein-protein interactions (PPIs). The SH2 domain specifically recognizes phosphotyrosine residues in other proteins, allowing BTK to interact with downstream signaling partners. Meanwhile, the SH3 domain mediates interactions with proline-rich regions in binding partners [[10], [11], [12], [13], [14]]. These domains collectively contribute to the versatility of BTKs in signal transduction and their involvement in a wide range of cellular processes.

The TH domain, located adjacent to the PH domain, plays a significant role in BTK stability and protein interactions. A zinc-finger motif found within the TH domain enhances structural stability of the protein and contributes to its binding affinity to certain partners [13]. The interaction between BTK and PIP3 at the plasma membrane is a crucial step in initiating BTK activation [10,11]. Following this interaction, a cytoplasmic kinase is briefly recruited to the plasma membrane, leading to the activation of the BTK kinase domain through phosphorylation by either spleen tyrosine kinase (SYK) or SRC kinase at Tyr551 [13]. This activation triggers downstream signaling cascades, including the Nuclear Factor kappa B (NF–κB) and nuclear receptor of activated T cells (NFAT) pathways, which significantly influence B cell signaling proteins.

The inhibition of BTKs holds great promise for the treatment of CLL and other B cell malignancies. Researchers have developed so far both covalent and non-covalent BTK inhibitors (BTKi) to target BTK for therapeutic purposes [15,16]. Notably, the FDA-approved covalent BTK inhibitors Ibrutinib, Zanubrutinib, and Acalabrutinib have revolutionized the treatment of B cell malignancies, demonstrating exceptional and durable success [17]. Fig. 1 illustrates the process of covalent binding between Ibrutinib and BTKs in the cytoplasm of B lymphocytes, effectively blocking the activity of BTKs. Of noteworthy mention is Ibrutinib, a covalent inhibitor of BTKs marketed as Imbruvica®, which has garnered considerable attention in recent years. Recognized for its exceptional efficacy in treating CLL, Ibrutinib ranked among the top 5 of the 100 best-selling compounds in 2022. The projected growth in the drug market by 2026 underscores the urgency to unravel the intricate mechanisms of BTKs for the development of efficient BTK-targeted therapeutics [[2], [3], [4]]. However, the development of resistance or intolerance to covalent BTKi in some patients necessitates the exploration of diverse covalent inhibitors to address this challenge effectively.

Understanding the intricate mechanisms of BTKs is vital for the development of efficient targeted therapies for cancer and B cell malignancies, with a particular focus on CLL. Moreover, the exploration of novel BTK inhibitors through diverse computational and experimental approaches is a critical step towards advancing targeted therapies and improving the prognosis for patients with B cell malignancies, particularly CLL. The continuous efforts to unravel the complexities of BTKs and their inhibitors hold great promise for advancing precision medicine and improving cancer treatment strategies [[18], [19], [20]].