Activin receptor-like kinases 1-7 (ALK1-7) regulate a complex network of SMAD-independent as well as SMAD-dependent signaling pathways. One of the widely used inhibitors for functional investigations of these processes, in particular for bone morphogenetic protein (BMP) signaling, is LDN-193189. However, LDN-193189 has insufficient kinome-wide selectivity complicating its use in cellular target validation assays. Herein, we report the identification and comprehensive characterization of two chemically distinct highly selective inhibitors of ALK1 and ALK2, M4K2234 and MU1700, along with their negative controls. We show that both MU1700 and M4K2234 efficiently block the BMP pathway via selective in cellulo inhibition of ALK1/2 kinases and exhibit favorable in vivo profiles in mice. MU1700 is highly brain penetrant and shows remarkably high accumulation in the brain. These high-quality orthogonal chemical probes offer the selectivity required to become widely used tools for in vitro and in vivo investigation of BMP signaling.

• MeSH
• aktivinové receptory typu I antagonisté a inhibitory   metabolismus   MeSH
• aktivinové receptory typu II * metabolismus   antagonisté a inhibitory   MeSH
• inhibitory proteinkinas farmakologie   chemie   MeSH
• kostní morfogenetické proteiny metabolismus   MeSH
• lidé MeSH
• molekulární sondy chemie   MeSH
• myši MeSH
• objevování léků MeSH
• pyrazoly chemie   farmakologie   chemická syntéza   MeSH
• signální transdukce účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aktivinové receptory typu I MeSH
• aktivinové receptory typu II * MeSH
• inhibitory proteinkinas MeSH
• kostní morfogenetické proteiny MeSH
• molekulární sondy MeSH
• pyrazoly MeSH