Detailed Information

Cited 0 time in webofscience Cited 0 time in scopus
Metadata Downloads

Discovery of 5-Phenoxy-2-aminopyridine Derivatives as Potent and Selective Irreversible Inhibitors of Bruton's Tyrosine Kinase

Authors
Lee, EunCho, HyewonLee, Da KyungHa, JuHyunChoi, Byeong JoJeong, Ji HyeRyu, Jae-HaKang, Jong SoonJeon, Raok
Issue Date
Nov-2020
Publisher
MDPI
Citation
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v.21, no.21, pp 1 - 15
Pages
15
Journal Title
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume
21
Number
21
Start Page
1
End Page
15
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/1072
DOI
10.3390/ijms21218006
ISSN
1661-6596
1422-0067
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.
Files in This Item
Go to Link
Appears in
Collections
약학대학 > 약학부 > 1. Journal Articles

qrcode

Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.

Related Researcher

Researcher Ryu, Jae Ha photo

Ryu, Jae Ha
약학대학 (약학부)
Read more

Altmetrics

Total Views & Downloads

BROWSE