Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L-783277
- Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L-783277
- 심태보; 허우영; 최환근; 전성훈; 조한나; Sandip Sengupta; 서홍석; 이병우; 김정훈; 정민환; 전누리; 김남두
- Issue Date
- Journal of medicinal chemistry
- VOL 60, NO 4-1508
- 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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