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Article

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

1
College of Pharmacy, Sookmyung Women’s University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, Korea
2
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, 80 Chembok-ro, Dong-gu, Daegu 41061, Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(21), 7919; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217919
Received: 12 August 2020 / Revised: 11 October 2020 / Accepted: 21 October 2020 / Published: 25 October 2020
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. View Full-Text
Keywords: pyranochromenone; BTK inhibitor; irreversible inhibitor; rheumatoid arthritis pyranochromenone; BTK inhibitor; irreversible inhibitor; rheumatoid arthritis
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MDPI and ACS Style

Cho, H.; Lee, E.; Kwon, H.A.; Seul, L.; Jeon, H.-J.; Yu, J.H.; Ryu, J.-H.; Jeon, R. Discovery of Tricyclic Pyranochromenone as Novel Bruton’s Tyrosine Kinase Inhibitors with In Vivo Antirheumatic Activity. Int. J. Mol. Sci. 2020, 21, 7919. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217919

AMA Style

Cho H, Lee E, Kwon HA, Seul L, Jeon H-J, Yu JH, Ryu J-H, Jeon R. Discovery of Tricyclic Pyranochromenone as Novel Bruton’s Tyrosine Kinase Inhibitors with In Vivo Antirheumatic Activity. International Journal of Molecular Sciences. 2020; 21(21):7919. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217919

Chicago/Turabian Style

Cho, Hyewon, Eun Lee, Hye A. Kwon, Lee Seul, Hui-Jeon Jeon, Ji H. Yu, Jae-Ha Ryu, and Raok Jeon. 2020. "Discovery of Tricyclic Pyranochromenone as Novel Bruton’s Tyrosine Kinase Inhibitors with In Vivo Antirheumatic Activity" International Journal of Molecular Sciences 21, no. 21: 7919. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217919

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