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Discovery of 5-Phenoxy-2-aminopyridine Derivatives as Potent and Selective Irreversible Inhibitors of Bruton’s Tyrosine Kinase
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 achiev...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663149/ https://www.ncbi.nlm.nih.gov/pubmed/33126415 http://dx.doi.org/10.3390/ijms21218006 |
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author | Lee, Eun Cho, Hyewon Lee, Da Kyung Ha, JuHyun Choi, Byeong Jo Jeong, Ji Hye Ryu, Jae-Ha Kang, Jong Soon Jeon, Raok |
author_facet | Lee, Eun Cho, Hyewon Lee, Da Kyung Ha, JuHyun Choi, Byeong Jo Jeong, Ji Hye Ryu, Jae-Ha Kang, Jong Soon Jeon, Raok |
author_sort | Lee, Eun |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7663149 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76631492020-11-14 Discovery of 5-Phenoxy-2-aminopyridine Derivatives as Potent and Selective Irreversible Inhibitors of Bruton’s Tyrosine Kinase Lee, Eun Cho, Hyewon Lee, Da Kyung Ha, JuHyun Choi, Byeong Jo Jeong, Ji Hye Ryu, Jae-Ha Kang, Jong Soon Jeon, Raok Int J Mol Sci Article 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. MDPI 2020-10-28 /pmc/articles/PMC7663149/ /pubmed/33126415 http://dx.doi.org/10.3390/ijms21218006 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lee, Eun Cho, Hyewon Lee, Da Kyung Ha, JuHyun Choi, Byeong Jo Jeong, Ji Hye Ryu, Jae-Ha Kang, Jong Soon Jeon, Raok Discovery of 5-Phenoxy-2-aminopyridine Derivatives as Potent and Selective Irreversible Inhibitors of Bruton’s Tyrosine Kinase |
title | Discovery of 5-Phenoxy-2-aminopyridine Derivatives as Potent and Selective Irreversible Inhibitors of Bruton’s Tyrosine Kinase |
title_full | Discovery of 5-Phenoxy-2-aminopyridine Derivatives as Potent and Selective Irreversible Inhibitors of Bruton’s Tyrosine Kinase |
title_fullStr | Discovery of 5-Phenoxy-2-aminopyridine Derivatives as Potent and Selective Irreversible Inhibitors of Bruton’s Tyrosine Kinase |
title_full_unstemmed | Discovery of 5-Phenoxy-2-aminopyridine Derivatives as Potent and Selective Irreversible Inhibitors of Bruton’s Tyrosine Kinase |
title_short | Discovery of 5-Phenoxy-2-aminopyridine Derivatives as Potent and Selective Irreversible Inhibitors of Bruton’s Tyrosine Kinase |
title_sort | discovery of 5-phenoxy-2-aminopyridine derivatives as potent and selective irreversible inhibitors of bruton’s tyrosine kinase |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663149/ https://www.ncbi.nlm.nih.gov/pubmed/33126415 http://dx.doi.org/10.3390/ijms21218006 |
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