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

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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