A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo.
A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo.
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DOI：
10.1371/journal.pone.0042120
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wang B
中科院分区：
文献类型：
--
作者：
Petty A;Myshkin E;Qin H;Guo H;Miao H;Tochtrop GP;Hsieh JT;Page P;Liu L;Lindner DJ;Acharya C;MacKerell AD Jr;Ficker E;Song J;Wang B
在肿瘤进展过程中，由于Akt激活和ephrin-A配体结合减少，EphA2受体可以获得不依赖于配体的促癌功能。这种作用可以通过配体刺激逆转，从而触发EphA2固有的肿瘤抑制信号通路，包括抑制PI3/Akt和Ras/ERK通路。这些观察结果支持开发EphA2小分子激动剂作为潜在的肿瘤干预剂。通过虚拟筛选和基于细胞的实验，我们在这里报告了doxazosin作为EphA2和EphA4的新型小分子激动剂的鉴定和表征，而不是其他Eph受体的激动剂。核磁共振研究揭示了doxazosin与EphA2/A4的广泛接触，概括了最近在EphA2/ephrin-A1复合体中发现的疏水和静电相互作用。doxazosin在临床上作为α1-肾上腺素受体拮抗剂（Cardura®）用于治疗高血压和良性前列腺增生，可激活独立于α1-肾上腺素受体的EphA2。与ephrin-A1类似，doxazosin以epha2依赖性的方式抑制Akt和ERK激酶的活性。doxazosin治疗可触发EphA2受体内化，抑制前列腺癌、乳腺癌和胶质瘤细胞的趋化和趋化迁移。此外，在原位异种移植模型中，doxazosin减少了人前列腺癌细胞的远端转移，延长了受体小鼠的存活时间。据我们所知，doxazosin是第一个能够在体外和体内抑制恶性行为的受体酪氨酸激酶的小分子激动剂。
During tumor progression, EphA2 receptor can gain ligand-independent pro-oncogenic functions due to Akt activation and reduced ephrin-A ligand engagement. The effects can be reversed by ligand stimulation, which triggers the intrinsic tumor suppressive signaling pathways of EphA2 including inhibition of PI3/Akt and Ras/ERK pathways. These observations argue for development of small molecule agonists for EphA2 as potential tumor intervention agents. Through virtual screening and cell-based assays, we report here the identification and characterization of doxazosin as a novel small molecule agonist for EphA2 and EphA4, but not for other Eph receptors tested. NMR studies revealed extensive contacts of doxazosin with EphA2/A4, recapitulating both hydrophobic and electrostatic interactions recently found in the EphA2/ephrin-A1 complex. Clinically used as an α1-adrenoreceptor antagonist (Cardura®) for treating hypertension and benign prostate hyperplasia, doxazosin activated EphA2 independent of α1-adrenoreceptor. Similar to ephrin-A1, doxazosin inhibited Akt and ERK kinase activities in an EphA2-dependent manner. Treatment with doxazosin triggered EphA2 receptor internalization, and suppressed haptotactic and chemotactic migration of prostate cancer, breast cancer, and glioma cells. Moreover, in an orthotopic xenograft model, doxazosin reduced distal metastasis of human prostate cancer cells and prolonged survival in recipient mice. To our knowledge, doxazosin is the first small molecule agonist of a receptor tyrosine kinase that is capable of inhibiting malignant behaviors in vitro and in vivo.
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影响因子：
64.8
作者：
Himanen, JP;Rajashankar, KR;Nikolov, DB
通讯作者：
Nikolov, DB
影响因子：
56.9
作者：
CONNOLLY, ML
通讯作者：
CONNOLLY, ML
影响因子：
25
作者：
Himanen, JP;Chumley, MJ;Nikolov, DB
通讯作者：
Nikolov, DB
DOI：
10.1107/s0907444902000264
发表时间：
2002-03-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Himanen, JP;Nikolov, DB
通讯作者：
Nikolov, DB
影响因子：
4.8
作者：
Miao, H;Strebhardt, K;Wang, BC
通讯作者：
Wang, BC