Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L-783277
- Authors
- Cho, Hanna; Sengupta, Sandip; Jeon, Sean S. H.; Hur, Wooyoung; Choi, Hwan Geun; Seo, Hong-Seog; Lee, Byung Joo; Kim, Jeong Hun; Chung, Minhwan; Jeon, Noo Li; Kim, Nam Doo; Sim, Taebo
- Issue Date
- 23-2월-2017
- Publisher
- AMER CHEMICAL SOC
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY, v.60, no.4, pp.1495 - 1508
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- Volume
- 60
- Number
- 4
- Start Page
- 1495
- End Page
- 1508
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/84408
- DOI
- 10.1021/acs.jmedchem.6b01679
- ISSN
- 0022-2623
- Abstract
- We synthesized 1 (San78-130), a reversible version of L-783277, as a selective and potent ALK1 inhibitor. Our study showed that 1 possesses great kinase selectivity against a panel of 342 kinases and more potent activity against ALK1 than L-783277. Among the six ALK isotypes (ALK1-6), ALK1 is most significantly inhibited by compound 1. Compound 1 suppresses the BMP9-induced Smad1/5 pathway by mainly inhibiting ALK1 in C2C12 cells. Our molecular dynamics simulations suggest that H-bonding interaction between the C-4' hydroxyl group of 1 and Arg334 of ALK1 substantially contributes to the ALK1 inhibition. To the best of our knowledge, 1 is the first selective ALK1 inhibitor. Furthermore, compound 1 promoted angiogenesis in both endothelial tube formation and microfluidic chip based 3D angiogenesis assays, suggesting that 1 could be a lead compound for therapeutic angiogenesis agents. Our study may provide an insight into designing selective and potent inhibitors against ALK1.
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Collections - Graduate School > Department of Biomedical Sciences > 1. Journal Articles
- Graduate School > KU-KIST Graduate School of Converging Science and Technology > 1. Journal Articles
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