Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases

Abstract

Bruton’s tyrosine kinase (BTK) plays a crucial role in B-cell receptor and Fc receptor signaling pathways. BTK is also involved in the regulation of Toll-like receptors and chemokine receptors. Given the central role of BTK in immunity, BTK inhibition represents a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. Great efforts have been made in developing BTK inhibitors for potential clinical applications in inflammatory and autoimmune diseases. This review covers the recent development of BTK inhibitors at preclinical and clinical stages in treating these diseases. Individual examples of three types of inhibitors, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors, are discussed with a focus on their structure, bioactivity and selectivity. Contrary to expectations, reversible BTK inhibitors have not yielded a significant breakthrough so far. The development of covalent, irreversible BTK inhibitors has progressed more rapidly. Many candidates entered different stages of clinical trials; tolebrutinib and evobrutinib are undergoing phase 3 clinical evaluation. Rilzabrutinib, a covalent reversible BTK inhibitor, is now in phase 3 clinical trials and also offers a promising future. An analysis of the protein–inhibitor interactions based on published co-crystal structures provides useful clues for the rational design of safe and effective small-molecule BTK inhibitors.

Nucleolar and spindle associated protein 1 enhances chemoresistance through DNA damage repair pathway in chronic lymphocytic leukemia by binding with RAD51

“…The B-cell receptor (BCR) signaling pathway is aberrantly activated in the CLL, which makes BTKi an effective way for CLL patients’ treatment [ 52 ]. Activation of PI3K is associated with the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 1,4,5-trisphosphate (PIP3), which assists BTK phosphorylation [ 53 ]. It is indicated that NUSAP1 knockdown inhibited cell growth and metastasis via regulating BTG2/PI3K/AKT signaling in nonsmall-cell lung cancer [ 14 ].…”

The Development of BTK Inhibitors: A Five-Year Update

“…In fact, covalent and irreversible inhibitions increase the risk of off-target reactivity to biomolecules, resulting in immunotoxicity, mutagenicity, and hepatotoxicity. In addition, because it has been demonstrated that both B-cells and cells of the myeloid lineage are important in the development of MS, an increased interest in developing BTKIs for MS treatment has emerged [ 14 , 15 ].…”

“…In the past ten years, different chemical scaffolds have been deeply investigated and patented as BTKIs [ 4 , 13 ]. In particular, Feng in 2019 and, more recently, Liu and Zhang [ 13 , 15 , 23 ] reported complete reviews in which they summarized the most interesting compounds obtained by different companies and academic researchers that were the most useful in cancer therapy as well as in inflammatory and autoimmune diseases. Pyrimidines, 2,4-diaminopyrimidines, 1,3,5-triazines, and condensed structures such as pyrazolo-pyrimidines, pyrazolo-pyridines, pyrrolo-pyrimidines, pyrrolo-triazines, imidazo-pyrazines, imidazo-pyrimidines, imidazo-quinoxalines, and purines gave the best results.…”

“…The same authors recently published a review focused on BTKIs that were launched in the market and were under clinical evaluation [ 7 ]. While there is much data on the role of BTK in malignancies, BTKIs in clinical or in preclinical–clinical investigations have been very recently reported [ 13 , 15 , 23 ]. A systematic list of compounds in the early phases of study is not yet available.…”

Synthesis of Radiopharmaceuticals via “In-Loop” 11C-Carbonylation as Exemplified by the Radiolabeling of Inhibitors of Bruton's Tyrosine Kinase

“…From a myeloid tissue perspective, BTK plays a role in mast cell activation via the high-affinity IgE receptor (14). Given these roles, BTK inhibitors are being evaluated for the treatment of B-cell malignancies (15), as well as for inflammatory and autoimmune disorders (16), including RA (17) and MS (18).…”