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

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.