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

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

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KU-KIST Graduate School of Converging Science and Technology, Korea University , 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST) , 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
Cardiovascular Center, Korea University Guro Hospital , 80 Guro-dong, Guro-gu, Seoul 152-703, Republic of Korea.
Fight Against Angiogenesis-related Blindness Laboratory, Clinical Research Institute, Seoul National University Hospital , 101, Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea.
Department of Biomedical Sciences, College of Medicine, Seoul National University , 103, Daehakro, Jongro-gu, Seoul 03080, Republic of Korea.
Department of Ophthalmology, College of Medicine, Seoul National University , 101, Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea.
Mechanical Engineering, Seoul National University , 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea.
Daegu-Gyeongbuk Medical Innovation Foundation , 2387 dalgubeol-daero, Suseong-gu, Daegu 42019, Republic of Korea.


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.

[Indexed for MEDLINE]

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