Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective

Brullo, Chiara; Villa, Carla; Tasso, Bruno; Russo, Eleonora; Spallarossa, Andrea

doi:10.3390/ijms22147641

Cited by 36 publications

(37 citation statements)

References 78 publications

(102 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…BTK consists of 659 amino acids and five domains from the N-terminus to the C-terminus: the pleckstrin homology (PH) domain, the proline-rich TEC homology (TH) domain, the SRC homology (SH) domains (named SH3 and SH2), and finally the catalytic domain [ 7 , 10 ]. The PH domain mediates protein–phospholipid and protein–protein interactions, whereas and the TH domain contains a zinc finger motif important for protein activity and stability.…”

Section: Btkis: Their Classificationmentioning

confidence: 99%

“…Therefore, BTK inhibition causes a block of different down-stream cell signalling pathways strictly related to the development of B-cell malignancies, as well as autoimmune diseases [ 7 ]. Since the BTK structure and function were well defined in 1993 by Vetrie et al [ 8 ], BTK inhibitors (BTKIs) have been studied for the treatment of different haematological disorders (particularly of B-cell malignancies) [ 9 ] and of many autoimmune diseases; consequently, many investigations by industry and academia have been performed.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Development of BTK Inhibitors: A Five-Year Update

et al. 2021

Self Cite

View full text Add to dashboard Cite

Bruton’s tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using “BTK” and “BTK inhibitors” as keywords.

show abstract

Section: Btkis: Their Classificationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Development of BTK Inhibitors: A Five-Year Update

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Both PI3K and BTK are well established molecular targets in cancer and count with FDA approved drugs for the treatment of an array of malignant subtypes, but still deal with emerging cases of drug resistance and inability to promote complete remission when used as monotherapy for R/R malignancies. In this context, a study conducted by Davids et al investigated the outcome of patients under ibrutinib, a first-generation BTK inhibitor, and umbrasilib, a selective PI3K-δ inhibitor, combination therapy and determined that this treatment protocol is not only effective but also clinically safe and warrants further investigation to fully elucidate its potential in the clinical practice [ 96 , 153 , 154 ].…”

Section: Lymphoid Malignanciesmentioning

confidence: 99%

Kinase Inhibition in Relapsed/Refractory Leukemia and Lymphoma Settings: Recent Prospects into Clinical Investigations

et al. 2021

View full text Add to dashboard Cite

Cancer is still a major barrier to life expectancy increase worldwide, and hematologic neoplasms represent a relevant percentage of cancer incidence rates. Tumor dependence of continuous proliferative signals mediated through protein kinases overexpression instigated increased strategies of kinase inhibition in the oncologic practice over the last couple decades, and in this review, we focused our discussion on relevant clinical trials of the past five years that investigated kinase inhibitor (KI) usage in patients afflicted with relapsed/refractory (R/R) hematologic malignancies as well as in the pharmacological characteristics of available KIs and the dissertation about traditional chemotherapy treatment approaches and its hindrances. A trend towards investigations on KI usage for the treatment of chronic lymphoid leukemia and acute myeloid leukemia in R/R settings was observed, and it likely reflects the existence of already established treatment protocols for chronic myeloid leukemia and acute lymphoid leukemia patient cohorts. Overall, regimens of KI treatment are clinically manageable, and results are especially effective when allied with tumor genetic profiles, giving rise to encouraging future prospects of an era where chemotherapy-free treatment regimens are a reality for many oncologic patients.

show abstract

“…Aberrant activation of B cells is demonstrated to play a central role in the pathogenesis of B-cell malignancies, autoimmune diseases and inflammation [ 5 , 6 ]. 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 Drug Administration (FDA) in 2013 to control a variety of B-cell tumors [ 5 , 7 , 8 , 9 , 10 ]. BTK is also involved in the activation of innate immune cells, including macrophages, neutrophils, mast cells and basophils.…”

Section: Introductionmentioning

confidence: 99%

“…For over a decade, there have been great efforts devoted to developing BTK inhibitors for potential clinical application in chronic inflammatory diseases and autoimmune diseases, in addition to hematologic malignancies [ 8 , 9 , 10 ]. Studies demonstrated that B cells are crucial players in inflammatory and autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren’s syndrome (SS), and multiple sclerosis (MS) [ 20 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Meng

2021

Molecules

View full text Add to dashboard Cite

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.

show abstract

Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective

Cited by 36 publications

References 78 publications

The Development of BTK Inhibitors: A Five-Year Update

The Development of BTK Inhibitors: A Five-Year Update

Kinase Inhibition in Relapsed/Refractory Leukemia and Lymphoma Settings: Recent Prospects into Clinical Investigations

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

Contact Info

Product

Resources

About