A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis.
A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis.
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DOI：
10.1007/s10456-014-9457-y
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发表时间：
2015-04
期刊：
影响因子：
9.8
通讯作者：
Harris, Adrian L.
中科院分区：
文献类型：
--
作者：
Kerr, Georgina;Sheldon, Helen;Chaikuad, Apirat;Alfano, Ivan;von Delft, Frank;Bullock, Alex N.;Harris, Adrian L.
激活素受体样激酶1由ACVRL1基因编码，是一种骨形态发生蛋白/转化生长因子-β受体，通过Smad1/5/8的磷酸化介导内皮细胞的信号传导。在茎细胞中，ALK1与Notch协同作用，诱导Notch靶标HEY1和HEY2的表达，从而抑制TIP细胞的形成和血管生成的萌发。ALK1-Fc可溶性蛋白融合已进入临床试验，作为隔离高亲和力细胞外配体BMP9的治疗策略。在这里，我们确定了ALK1细胞内激活域的晶体结构，并探讨了小分子激酶抑制剂K02288对血管生成的影响。K02288抑制BMP9诱导的人脐静脉内皮细胞Smad1/5/8的磷酸化，以减少SMAD和Notch依赖的转录反应。在内皮细胞萌发试验中，K02288处理诱导了一种使人想起Notch抑制的过度萌发表型。此外，K02288在鸡绒毛膜尿囊膜血管生成实验中引起了功能障碍的血管形成。这种活性对于目前处于临床前开发的小分子抑制剂可能是有利的，以获得特定的BMP功能条件，包括弥漫性固有桥脑胶质瘤和进行性骨化纤维发育不良，以及更广泛地用于肿瘤生物学的其他应用。
Activin receptor-like kinase 1 (ALK1, encoded by the gene ACVRL1) is a type I BMP/TGF-β receptor that mediates signalling in endothelial cells via phosphorylation of SMAD1/5/8. During angiogenesis, sprouting endothelial cells specialise into tip cells and stalk cells. ALK1 synergises with Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2 and thereby represses tip cell formation and angiogenic sprouting. The ALK1-Fc soluble protein fusion has entered clinic trials as a therapeutic strategy to sequester the high-affinity extracellular ligand BMP9. Here, we determined the crystal structure of the ALK1 intracellular kinase domain and explored the effects of a small molecule kinase inhibitor K02288 on angiogenesis. K02288 inhibited BMP9-induced phosphorylation of SMAD1/5/8 in human umbilical vein endothelial cells to reduce both the SMAD and the Notch-dependent transcriptional responses. In endothelial sprouting assays, K02288 treatment induced a hypersprouting phenotype reminiscent of Notch inhibition. Furthermore, K02288 caused dysfunctional vessel formation in a chick chorioallantoic membrane assay of angiogenesis. Such activity may be advantageous for small molecule inhibitors currently in preclinical development for specific BMP gain of function conditions, including diffuse intrinsic pontine glioma and fibrodysplasia ossificans progressiva, as well as more generally for other applications in tumour biology.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
4.8
作者：
Upton, Paul D.;Davies, Rachel J.;Morrell, Nicholas W.
通讯作者：
Morrell, Nicholas W.
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
30.8
作者：
Shore, EM;Xu, MQ;Kaplan, FS
通讯作者：
Kaplan, FS
DOI：
10.1074/jbc.m112.365932
发表时间：
2012-10-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Chaikuad A;Alfano I;Kerr G;Sanvitale CE;Boergermann JH;Triffitt JT;von Delft F;Knapp S;Knaus P;Bullock AN
通讯作者：
Bullock AN