Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L-783277

Hanna Cho, Sandip Sengupta, Sean S H Jeon, Wooyoung Hur, Hwan Geun Choi, Hong Seog Seo, Byung Joo Lee, Jeong Hun Kim, Minhwan Chung, Noo Li Jeon, Nam Doo Kim, Taebo Sim

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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.

Original languageEnglish
Pages (from-to)1495-1508
Number of pages14
JournalJournal of Medicinal Chemistry
Volume60
Issue number4
DOIs
Publication statusPublished - 2017 Feb 23

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Activin Receptors
Phosphotransferases
Microfluidics
Molecular Dynamics Simulation
Hydroxyl Radical
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L-783277. / 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.

In: Journal of Medicinal Chemistry, Vol. 60, No. 4, 23.02.2017, p. 1495-1508.

Research output: Contribution to journalArticle

Cho, H, Sengupta, S, Jeon, SSH, Hur, W, Choi, HG, Seo, HS, Lee, BJ, Kim, JH, Chung, M, Jeon, NL, Kim, ND & Sim, T 2017, 'Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L-783277', Journal of Medicinal Chemistry, vol. 60, no. 4, pp. 1495-1508. https://doi.org/10.1021/acs.jmedchem.6b01679
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. / Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L-783277. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 4. pp. 1495-1508.
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