Discovery of a Series of 2,5-Diaminopyrimidine Covalent Irreversible Inhibitors of Bruton’s Tyrosine Kinase with in Vivo Antitumor Activity

2014 ◽  
Vol 57 (12) ◽  
pp. 5112-5128 ◽  
Author(s):  
Xitao Li ◽  
Yingying Zuo ◽  
Guanghui Tang ◽  
Yan Wang ◽  
Yiqing Zhou ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tyrosine Kinase ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Irreversible Inhibitors ◽  
In Vivo Antitumor Activity

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

2020 ◽  
Vol 21 (21) ◽  
pp. 8006
Author(s):  
Eun Lee ◽  
Hyewon Cho ◽  
Da Kyung Lee ◽  
JuHyun Ha ◽  
Byeong Jo Choi ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Unmet Need ◽  
Cell Receptor ◽  
Bruton’S Tyrosine Kinase ◽  
Type Ii ◽  
Irreversible Inhibitor ◽  
Bruton's Tyrosine Kinase ◽  
Irreversible Inhibitors ◽  
Btk Inhibitors

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.

scholarly journals Discovery of Tricyclic Pyranochromenone as Novel Bruton’s Tyrosine Kinase Inhibitors with In Vivo Antirheumatic Activity

2020 ◽  
Vol 21 (21) ◽  
pp. 7919
Author(s):  
Hyewon Cho ◽  
Eun Lee ◽  
Hye Ah Kwon ◽  
Lee Seul ◽  
Hui-Jeon Jeon ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Docking Study ◽  
Bruton’S Tyrosine Kinase ◽  
Collagen Induced Arthritis ◽  
Bruton's Tyrosine Kinase ◽  
Ic50 Values ◽  
Novel Scaffold ◽  
Btk Inhibitors

Bruton’s tyrosine kinase (BTK) is an attractive target for treating patients with B cell malignancies and autoimmune diseases. Many BTK inhibitors have been identified; however, like other kinase inhibitors, they lack diversity in their core structures. Therefore, it is important to secure a novel scaffold that occupies the adenine-binding site of BTK. We screened an in-house library of natural products and their analogs via a biochemical assay to identify a novel scaffold for targeting BTK. A pyranochromenone scaffold, derived from a natural active component decursin, was found to be effective at targeting BTK and was selected for further optimization. A series of pyranochromenone analogs was synthesized through the modification of pyranochromenone at the C7 position. Pyranochromenone compounds with an electrophilic warhead exhibited promising BTK inhibitory activity, with IC50 values in the range of 0.5–0.9 µM. A docking study of the representative compound 8 provided a reasonable explanation for compound activity. Compound 8 demonstrated good selectivity over other associated kinases and decreased the production of proinflammatory cytokines in THP cells. Moreover, compound 8 presented significant in vivo efficacy in a murine model of collagen-induced arthritis.

scholarly journals Silencing Bruton's tyrosine kinase in alveolar neutrophils protects mice from LPS/immune complex-induced acute lung injury

2014 ◽  
Vol 307 (6) ◽  
pp. L435-L448 ◽  
Author(s):  
Agnieszka Krupa ◽  
Marek Fol ◽  
Moshiur Rahman ◽  
Karen Y. Stokes ◽  
Jon M. Florence ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Tyrosine Kinase ◽  
Immune Complex ◽  
Distress Syndrome ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Neutrophil Survival

Previous observations made by our laboratory indicate that Bruton's tyrosine kinase (Btk) may play an important role in the pathophysiology of local inflammation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). We have shown that there is cross talk between FcγRIIa and TLR4 in alveolar neutrophils from patients with ALI/ARDS and that Btk mediates the molecular cooperation between these two receptors. To study the function of Btk in vivo we have developed a unique two-hit model of ALI: LPS/immune complex (IC)-induced ALI. Furthermore, we conjugated F(ab)2 fragments of anti-neutrophil antibodies (Ly6G1A8) with specific siRNA for Btk to silence Btk specifically in alveolar neutrophils. It should be stressed that we are the first group to perform noninvasive transfections of neutrophils, both in vitro and in vivo. Importantly, our present findings indicate that silencing Btk in alveolar neutrophils has a dramatic protective effect in mice with LPS/IC-induced ALI, and that Btk regulates neutrophil survival and clearance of apoptotic neutrophils in this model. In conclusion, we put forward a hypothesis that Btk-targeted neutrophil specific therapy is a valid goal of research geared toward restoring homeostasis in lungs of patients with ALI/ARDS.

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