Cho, Hanna Sengupta, Sandip Jeon, Sean S. H. Hur, Wooyoung Choi, Hwan Geun Seo, Hong-Seog Lee, Byung Joo Kim, Jeong Hun Chung, Minhwan Jeon, Noo Li Kim, Nam Doo Sim, Taebo 2024-01-20T02:03:19Z 2024-01-20T02:03:19Z 2022-01-10 2017-02-23 0022-2623 https://pubs.kist.re.kr/handle/201004/123047 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. English AMER CHEMICAL SOC BONE MORPHOGENETIC PROTEIN RESORCYLIC ACID LACTONES ABSOLUTE-CONFIGURATIONS NEGATIVE REGULATION ID PROTEINS ALK1 ANALOGS DIFFERENTIATION ANGIOGENESIS ACTIVATION Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L-783277 Article 10.1021/acs.jmedchem.6b01679 1 JOURNAL OF MEDICINAL CHEMISTRY, v.60, no.4, pp.1495 - 1508 JOURNAL OF MEDICINAL CHEMISTRY 60 4 1495 1508 scie scopus 000394924900018 2-s2.0-85013747095 Chemistry, Medicinal Pharmacology & Pharmacy Article BONE MORPHOGENETIC PROTEIN RESORCYLIC ACID LACTONES ABSOLUTE-CONFIGURATIONS NEGATIVE REGULATION ID PROTEINS ALK1 ANALOGS DIFFERENTIATION ANGIOGENESIS ACTIVATION ALK1