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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...

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Autores principales: Lee, Eun, Cho, Hyewon, Lee, Da Kyung, Ha, JuHyun, Choi, Byeong Jo, Jeong, Ji Hye, Ryu, Jae-Ha, Kang, Jong Soon, Jeon, Raok
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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.
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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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