title: Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L-783277.
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.
authors.affiliation: KU-KIST Graduate School of Converging Science and Technology, Korea University , 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Hanna
authors.initials: H
authors.lastname: Cho
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST) , 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
authors.forename: Sandip
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: KU-KIST Graduate School of Converging Science and Technology, Korea University , 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Sean S H
authors.initials: SS
authors.lastname: Jeon
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST) , 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Hur
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST) , 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.affiliation: KU-KIST Graduate School of Converging Science and Technology, Korea University , 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.|Cardiovascular Center, Korea University Guro Hospital , 80 Guro-dong, Guro-gu, Seoul 152-703, Republic of Korea.
authors.forename: Hong-Seog
authors.initials: HS
authors.lastname: Seo
authors.affiliation: 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.
authors.forename: Byung Joo
authors.initials: BJ
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Mechanical Engineering, Seoul National University , 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea.
authors.forename: Minhwan
authors.initials: M
authors.lastname: Chung
authors.affiliation: Mechanical Engineering, Seoul National University , 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea.
authors.forename: Noo Li
authors.initials: NL
authors.lastname: Jeon
authors.affiliation: Daegu-Gyeongbuk Medical Innovation Foundation , 2387 dalgubeol-daero, Suseong-gu, Daegu 42019, Republic of Korea.
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Taebo
authors.identifier: 0000-0003-3015-2059
authors.initials: T
authors.lastname: Sim
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D043925:Angiogenesis Inducing Agents / Q000737:chemistry / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D012118:Resorcinols / Q000737:chemistry* / Q000494:pharmacology*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; C405053:L 783277; D007783:Lactones; D047428:Protein Kinase Inhibitors; D012118:Resorcinols; D051785:Smad Proteins; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II