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 signaling and phosphorylate SMAD1/5/ 8 of SMAD family transcription factors[2]. DMH-1 is a selective inhibitor of BMP type I receptors with IC50 values of 107.9 nM for ALK2 and with no activity on ALK5, AMPK, VEGFR2 or PDGFRβ (measured by in vitro kinase assays). DMH1 on concentration of 1-20 μM blocked BMP4-induced Smad 1/5/8 phosphorylation dose-dependently in HEK293 cells. In contrast, DMH1 had no effect on BMP4-induced p38 MAPK phosphorylation or Activin A-induced Smad2 phosphorylation[1]. Mice expressing MMTV.PyVmT, with six-week pumps containing 7 mg DMH1, showed reduced lung metastasis and the tumors were less proliferative and more apoptotic compared with the control group[3]. DMH1 is also used in cell differentiation or reprogramming, for example: 1.Combined with SB431542, DMH1 can induce neuralization of hiPSCs[4]. 2. DMH1 can increase cardiomyocyte progenitors and promote cardiac differentiation in mouse embryonic stem cells[5].
作用机制
DMH-1 targets to the ATP-binding pocket located within the intracellular kinase domain of the receptors.[6]
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