Discovery of Tricyclic Pyranochromenone as Novel Bruton's Tyrosine Kinase Inhibitors with in Vivo Antirheumatic Activity

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 no...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 21; no. 21; p. 7919
Main Authors:	Cho, Hyewon, Lee, Eun, Kwon, Hye Ah, Seul, Lee, Jeon, Hui-Jeon, Yu, Ji Hoon, Ryu, Jae-Ha, Jeon, Raok
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 25-10-2020 MDPI
Subjects:	Adenine Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors Agammaglobulinaemia Tyrosine Kinase - chemistry Agammaglobulinaemia Tyrosine Kinase - metabolism Analogs Animal models Animals Antirheumatic Agents - chemistry Antirheumatic Agents - pharmacology Arthritis Arthritis, Experimental - prevention & control Autoimmune diseases Benzopyrans - chemistry Benzopyrans - pharmacology Binding sites Biological Products - chemistry Biological Products - pharmacology Bruton's tyrosine kinase BTK inhibitor Butyrates - chemistry Butyrates - pharmacology Collagen Cytokines Humans Inflammation irreversible inhibitor Kinases Male Mice, Inbred DBA Molecular Docking Simulation Molecular Structure Natural products Protein Domains Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein-tyrosine kinase pyranochromenone Rheumatoid arthritis Scaffolds Selectivity Structure-Activity Relationship THP-1 Cells Tyrosine United States > US irreversible inhibitor pyranochromenone BTK inhibitor rheumatoid arthritis
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Summary:	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 IC values in the range of 0.5-0.9 µM. A docking study of the representative compound provided a reasonable explanation for compound activity. Compound demonstrated good selectivity over other associated kinases and decreased the production of proinflammatory cytokines in THP cells. Moreover, compound presented significant in vivo efficacy in a murine model of collagen-induced arthritis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms21217919