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.
Highlights
Bruton’s tyrosine kinase (BTK) is a nonreceptor cytoplasmic tyrosine kinase in theTec family of protein tyrosine kinases
Great success has been achieved in the development of covalent irreversible BTK inhibitors for the treatment of hematological malignancies, as exemplified by ibrutinib, the first effective and selective BTK inhibitor approved by the Food and
This review provides a summary of the inhibitor-protein interactions based on the available structural data, supplying useful clues for the rational design and optimization of potent and specific small-molecule BTK inhibitors
Summary
Bruton’s tyrosine kinase (BTK) is a nonreceptor cytoplasmic tyrosine kinase in the. Tec family of protein tyrosine kinases. Given the central role of BTK in BCR and FcR signaling pathways as well as its important function in the regulation of TLRs and chemokine receptors, inhibition of BTK represents an attractive potential therapeutic approach for the treatment of autoimmune and inflammatory disorders in which B lymphocytes and myeloid cells induce or sustain an excessive autoimmune response. As a potent BTK inhibitor, ibrutinib exhibited therapeutic effects in both the collagen-induced arthritis (CIA) and collagen antibodyinduced arthritis (CAIA) rodent models of RA in a dose-dependent manner [29,30,31] It showed an inhibitory effect on FcγR- and FcεR-mediated cytokine release by monocytes, macrophages and mast cells [31]. This review will cover recent advances in the field of medicinal chemistry towards small-molecule BTK inhibitors under clinical trials for the treatment of inflammatory and autoimmune diseases, including RA, SS, MS, SLE, urticaria, pemphigus, ITP, and RD. Molecules 2021, 26, 4907 a comparison of the three design strategies demonstrates the good prospect of irreversible covalent and reversible covalent BTK inhibitors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
