Zebrafish models are well established tools for investigating underlying mechanisms of diseases. Here, we identified cercosporamide, a metabolite from the fungus Ascochyta aquiliqiae, as a potent bone morphogenetic protein receptor (BMPR) type I kinase inhibitor through a zebrafish embryo phenotypic screen. The developmental defects in zebrafish, including lack of the ventral fin induced by cercosporamide was strikingly similar as the phenotypes caused by renowned small molecule BMPR type I kinase inhibitors and inactivating mutations in zebrafish BMPRs. In mammalian cell-based assays, cercosporamide blocked BMP/SMAD-dependent transcriptional reporter activity and BMP-induced SMAD1/5-phosphorylation. Biochemical assays with a panel of purified recombinant kinases demonstrated that cercosporamide directly inhibited kinase activity of BMPRs type I (also called activin receptor-like kinases (ALKs)). In mammalian cells, cercosporamide selectively inhibited constitutively active BMPR type I-induced SMAD1/5 phosphorylation. Importantly, cercosporamide rescued the developmental defects caused by constitutively active Alk2 in zebrafish embryos. Taken together, we believe cercosporamide may be the first of a new class of molecules with potential to be developed further for clinical use against diseases that are causally linked to overactivation of BMPR signaling, including Fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma.

中文翻译：

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Cercosporamide 抑制斑马鱼骨形态发生蛋白受体 I 型激酶活性。


斑马鱼模型是研究疾病潜在机制的成熟工具。在这里，我们通过斑马鱼胚胎表型筛选，鉴定出尾孢菌酰胺（一种来自真菌Ascochyta aquiliqiae的代谢物）作为一种有效的骨形态发生蛋白受体 (BMPR) I 型激酶抑制剂。斑马鱼的发育缺陷，包括由尾孢酰胺引起的腹鳍缺失，与著名的小分子 BMPR I 型激酶抑制剂和斑马鱼 BMPR 失活突变引起的表型惊人地相似。在基于哺乳动物细胞的检测中，尾孢酰胺阻断 BMP/SMAD 依赖性转录报告活性和 BMP 诱导的 SMAD1/5 磷酸化。使用一组纯化的重组激酶进行的生化测定表明，尾孢酰胺直接抑制 I 型 BMPR（也称为激活素受体样激酶 (ALK)）的激酶活性。在哺乳动物细胞中，尾孢酰胺选择性抑制持续活跃的 BMPR I 型诱导的 SMAD1/5 磷酸化。重要的是，尾孢酰胺挽救了斑马鱼胚胎中由组成型活性 Alk2 引起的发育缺陷。综上所述，我们相信尾孢菌素可能是第一个新型分子，有可能进一步开发用于临床治疗与 BMPR 信号过度激活有因果关系的疾病，包括进行性骨化性纤维发育不良和弥漫性内源性脑桥神经胶质瘤。