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

J Med Chem. 2017 Feb 23;60(4):1495-1508. doi: 10.1021/acs.jmedchem.6b01679. Epub 2017 Feb 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / antagonists & inhibitors*
  • Activin Receptors, Type II / chemistry
  • Activin Receptors, Type II / metabolism
  • Amino Acid Sequence
  • Angiogenesis Inducing Agents / chemistry
  • Angiogenesis Inducing Agents / pharmacology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Lactones / chemistry*
  • Lactones / pharmacology*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Resorcinols / chemistry*
  • Resorcinols / pharmacology*
  • Sequence Alignment
  • Signal Transduction / drug effects
  • Smad Proteins / metabolism

Substances

  • Angiogenesis Inducing Agents
  • L 783277
  • Lactones
  • Protein Kinase Inhibitors
  • Resorcinols
  • Smad Proteins
  • ACVRL1 protein, human
  • Activin Receptors, Type II