生物活性

• 靶点

  ALK2 IC50:5nM

  ALK3 IC50:30nM

• 描述BMPs (Bone morphogenetic proteins) represent the largest subgroup in the TGFβ family of extracellular ligands. Their signaling transduction requires the interaction with the type I and type II transmembrane receptor kinase. Type I receptors, such as ALK1/ACVRL1, ALK2/ACVR1, ALK3/BMPR1A and ALK6/BMPR1B all participate in BMP signalling and phosphorylate SMAD1/5/ 8 phosphorylate SMAD family transcription factors. Dysregulation of this pathway links to many disease conditions, for example, fibrodysplasia ossificans progressive^[1]. LDN-193189 is a selective inhibitor of BMP type I receptors with IC50 values of 5 nM and 30 nM for ALK2 and ALK3 (measured by p-Smad1/5/8 in PASMCs), respectively, with substantially weaker effects on ALK4, ALK5 and ALK7 (IC50≥500 nM). PASMCs treated with LDN-193189 on concentration at 2 - 250 nM showed dose-dependent inhibition on p-Smad1/5/8 induced by BMP4 (10 ng/ml), while retaining 200-fold selectivity for BMP signaling versus TGF-β signaling (IC50≥1000 nM). Even LDN-193189 can block the transcriptional activity induced by either constitutively active ALK2^R206H or ALK2^Q207D mutant proteins. Intraperitoneal injection with LDN-193189 on dose of 3 mg/kg, every 12 h, resulted in a reduction in ectopic ossification and functional impairment in ALK2^Q207D mutant mice^[2]. Use of LDN-193189 combined with different small molecular led to the effective generation from ESCs of paraxial mesodermal progeny, and to their further differentiation in vitro through sclerotome specification into growth plate-like chondrocytes^[3]. Inhibition of BMP signaling by LDN-193189 can inhibit endothelial cell differentiation in the ventral blood island^[4].
• 作用机制LDN-193189 targets to the ATP-binding pocket located within the intracellular kinase domain of the receptors^[1].

• 动物研究
  剂量	Mice: 2.5 mg/kg[5] (i.p.), 10 mg/kg[6] (i.p.), max = 35 mg/kg[7] (p.o.)
  给药途径	i.p., p.o.
  动物药代数据	Animal Mice[8] Dose 3 mg/kg Administration i.p. Cmax 1.54 μM T1/2 1.6 h AUC∞ 994 ng·h/ml Tmax < 5 min