Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Dec 6;26(23):7411.
doi: 10.3390/molecules26237411.

The Development of BTK Inhibitors: A Five-Year Update

Bruno Tasso  1 , Andrea Spallarossa  1 , Eleonora Russo  1 , Chiara Brullo  1
Affiliations
Review

The Development of BTK Inhibitors: A Five-Year Update

Bruno Tasso et al. Molecules. .

Abstract

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.

Keywords: (ir)reversible inhibitors; B-cell malignancies; Bruton’s kinase; autoimmune diseases; medicinal chemistry; small molecules.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of irreversible BTKIs.
Figure 2
Figure 2
Superposition of Ibrutinib (orange, PDB code: 5P9J) and Zanubrutinib (green, PDB code: 6J6M) covalently bound to BTK Cys481.
Figure 3
Figure 3
Ligplot of the BTK-Branebrutinib crystallographic complex (PDB code: 6081).
Figure 4
Figure 4
(A) Schematic representation of interaction of BTK and Fenebrutinib; (B) Ligplot of BTK–Fenebrutinib crystallographic complex (PDB code: 5VFI).
Figure 5
Figure 5
DPPYs reported as BTKIs.
Figure 6
Figure 6
Pyrimidine, pyridine, pyridinone, and 1,3,5 triazine derivatives.
Figure 7
Figure 7
Pyrazolo-pyrimidine derivatives.
Figure 8
Figure 8
Thieno and pyrrolo-pyrimidine derivatives.
Figure 9
Figure 9
Imidazo-pyrazine, imidazo-pyridine and imidazo-pyrazole derivatives.
Figure 10
Figure 10
Quinoline, isoquinoline and phthalazine derivatives.
Figure 11
Figure 11
Carbazole, tetrahydrocarbazole and indole derivatives.
Figure 12
Figure 12
Miscellaneus derivatives.
Figure 13
Figure 13
PROTAC derivatives.
See this image and copyright information in PMC

References

    1. Carnero Contentti E., Correale J. Bruton’s tyrosine kinase inhibitors: A promising emerging treatment option for multiple sclerosis. Expert Opin. Emerg. Drugs. 2020;25:377–381. doi: 10.1080/14728214.2020.1822817. - DOI - PubMed
    1. Byrd J.C., Furman R.R., Coutre S.E., Flinn I.W., Burger J.A., Blum K.A., Grant B., Sharman J.P., Coleman M., Wierda W.G., et al. Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia. N. Engl. J. Med. 2013;369:32–42. doi: 10.1056/NEJMoa1215637. - DOI - PMC - PubMed
    1. Zhao Y., Bilal M., Raza A., Khan M.I., Mehmood S., Hayat U., Hassan S.T.S., Iqbal H.M.N. Tyrosine kinase inhibitors and their unique therapeutic potentialities to combat cancer. Int. J. Biol. Macromol. 2020;168:22–37. doi: 10.1016/j.ijbiomac.2020.12.009. - DOI - PubMed
    1. Liang C., Tian D., Ren X., Ding S., Jia M., Xin M., Thareja S. The development of Bruton’s tyrosine kinase (BTK) inhibitors from 2012 to 2017: A mini-review. Eur. J. Med. Chem. 2018;151:315–326. doi: 10.1016/j.ejmech.2018.03.062. - DOI - PubMed
    1. Jongstra-Bilen J., Cano A.P., Hasija M., Xiao H., Smith C.I.E., Cybulsky M. Dual Functions of Bruton’s Tyrosine Kinase and Tec Kinase during Fcγ Receptor-Induced Signaling and Phagocytosis. J. Immunol. 2008;181:288–298. doi: 10.4049/jimmunol.181.1.288. - DOI - PubMed

MeSH terms

Substances