|
|
| Type |
Poster Presentation |
| Area |
의약화학 |
| Room No. |
포스터발표장 |
| Time |
4월 20일 (목요일) 11:00~12:30 |
| Code |
MEDI.P-454 |
| Subject |
Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor, a Reversible Version of L‑783277 [우수포스터상] |
| Authors |
조한나, 심태보1,*
고려대학교 KU-KIST, Korea
1한국과학기술연구원(KIST) 화학키노믹스연구센터, Korea
|
| 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. |
| E-mail |
nanhannada@gmail.com |
|
119th General Meeting of the KCS