Discovery of 5-phenoxy-2-aminopyridine derivatives as potent and selective irreversible inhibitors of Bruton’s tyrosine kinase

Cited 1 time in scopus
Metadata Downloads
Title
Discovery of 5-phenoxy-2-aminopyridine derivatives as potent and selective irreversible inhibitors of Bruton’s tyrosine kinase
Author(s)
E Lee; H Cho; D K Lee; J Ha; Byeong Jo Choi; J H Jeong; J H Ryu; Jong Soon Kang; R Jeon
Bibliographic Citation
International Journal of Molecular Sciences, vol. 21, pp. 8006-8006
Publication Year
2020
Abstract
As a member of the tyrosine protein kinase Tec (TEC) family, Bruton's tyrosine kinase (BTK) is considered a promising therapeutic target due to its crucial roles in the B cell receptor (BCR) signaling pathway. Although many types of BTK inhibitors have been reported, there is an unmet need to achieve selective BTK inhibitors to reduce side effects. To obtain BTK selectivity and efficacy, we designed a novel series of type II BTK inhibitors which can occupy the allosteric pocket induced by the DFG-out conformation and introduced an electrophilic warhead for targeting Cys481. In this article, we have described the structure-activity relationships (SARs) leading to a novel series of potent and selective piperazine and tetrahydroisoquinoline linked 5-phenoxy-2-aminopyridine irreversible inhibitors of BTK. Compound 18g showed good potency and selectivity, and its biological activity was evaluated in hematological tumor cell lines. The in vivo efficacy of 18g was also tested in a Raji xenograft mouse model, and it significantly reduced tumor size, with 46.8% inhibition compared with vehicle. Therefore, we have presented the novel, potent, and selective irreversible inhibitor 18g as a type II BTK inhibitor.
Keyword
Bruton’s tyrosine kinaseirreversible kinase inhibitorhematological malignancy
ISSN
1422-0067
Publisher
MDPI
DOI
http://dx.doi.org/10.3390/ijms21218006
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
Files in This Item:

Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.