Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations.
Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations.
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Ponatinib (AP24534) 抑制 MEKK3-KLF 信号传导并预防脑海绵状血管瘤的形成和进展
DOI：
10.1126/sciadv.aau0731
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发表时间：
2018-11
期刊：
影响因子：
13.6
通讯作者：
Zheng X
中科院分区：
文献类型：
--
作者：
Choi JP;Wang R;Yang X;Wang X;Wang L;Ting KK;Foley M;Cogger V;Yang Z;Liu F;Han Z;Liu R;Baell J;Zheng X
泊那替尼是一种抗癌药物，可抑制小鼠模型中脑海绵状血管畸形的发生和生长。脑海绵状血管畸形（CCM）是一种常见的脑血管疾病，可以发生零星或遗传。它们是年轻人群中中风、脑出血和神经功能缺损的主要原因。三种基因CCM 1、CCM 2和CCM 3的功能缺失突变已被确定为人类CCM的原因。目前，没有药物可用于治疗CCM疾病。由于CCM基因丢失导致的过度活跃的丝裂原活化蛋白激酶3（MEKK 3）激酶信号传导是CCM病变发展的根本原因。使用美国食品和药物管理局批准的激酶抑制剂库，结合虚拟建模和生物化学和细胞测定，我们已经确定了一种临床批准的小化合物，泊那替尼，能够抑制MEKK 3活性并使下游Kruppel样因子（KLF）靶基因的表达正常化。在CCM的新生小鼠模型中用该化合物治疗可以防止新的CCM病变的形成并减少已经形成的病变的生长。在超细胞水平，泊那替尼可以使CCM缺乏引起的内皮扁平化和解体正常化。总的来说，我们的研究表明帕纳替尼是一种新型化合物，可以通过抑制MEKK 3-KLF信号传导来预防小鼠模型中的CCM发生和进展。
Ponatinib, a cancer drug, inhibits occurrence and growth of cerebral cavernous malformation in mouse models. Cerebral cavernous malformation (CCM) is a common cerebrovascular disease that can occur sporadically or be inherited. They are major causes of stroke, cerebral hemorrhage, and neurological deficits in the younger population. Loss-of-function mutations in three genes, CCM1, CCM2, and CCM3, have been identified as the cause of human CCMs. Currently, no drug is available to treat CCM disease. Hyperactive mitogen-activated protein kinase kinase Kinase 3 (MEKK3) kinase signaling as a consequence of loss of CCM genes is an underlying cause of CCM lesion development. Using a U.S. Food and Drug Administration–approved kinase inhibitor library combined with virtual modeling and biochemical and cellular assays, we have identified a clinically approved small compound, ponatinib, that is capable of inhibiting MEKK3 activity and normalizing expression of downstream kruppel-like factor (KLF) target genes. Treatment with this compound in neonatal mouse models of CCM can prevent the formation of new CCM lesions and reduce the growth of already formed lesions. At the ultracellular level, ponatinib can normalize the flattening and disorganization of the endothelium caused by CCM deficiency. Collectively, our study demonstrates ponatinib as a novel compound that may prevent CCM initiation and progression in mouse models through inhibition of MEKK3-KLF signaling.
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影响因子：
3.7
作者：
Choi JP;Foley M;Zhou Z;Wong WY;Gokoolparsadh N;Arthur JS;Li DY;Zheng X
通讯作者：
Zheng X
影响因子：
46.9
作者：
通讯作者：
--
DOI：
10.1038/nrm3176
发表时间：
2011-08-23
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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影响因子：
4.2
作者：
Karpov, Alexei S.;Amiri, Payman;Marzinzik, Andreas L.
通讯作者：
Marzinzik, Andreas L.
影响因子：
5.7
作者：
Tucker, Julie A.;Klein, Tobias;Norman, Richard A.
通讯作者：
Norman, Richard A.