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

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...

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Autores principales: Zhang, Datong, Gong, He, Meng, Fancui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399599/
https://www.ncbi.nlm.nih.gov/pubmed/34443496
http://dx.doi.org/10.3390/molecules26164907
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author Zhang, Datong
Gong, He
Meng, Fancui
author_facet Zhang, Datong
Gong, He
Meng, Fancui
author_sort Zhang, Datong
collection PubMed
description 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.
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spelling pubmed-83995992021-08-29 Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases Zhang, Datong Gong, He Meng, Fancui Molecules Review 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. MDPI 2021-08-13 /pmc/articles/PMC8399599/ /pubmed/34443496 http://dx.doi.org/10.3390/molecules26164907 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Zhang, Datong
Gong, He
Meng, Fancui
Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases
title Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases
title_full Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases
title_fullStr Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases
title_full_unstemmed Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases
title_short Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases
title_sort recent advances in btk inhibitors for the treatment of inflammatory and autoimmune diseases
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399599/
https://www.ncbi.nlm.nih.gov/pubmed/34443496
http://dx.doi.org/10.3390/molecules26164907
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