Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor.
Pin1 inhibition improves the efficacy of ralaniten compounds that bind to the N-terminal domain of androgen receptor.
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Pin 1抑制提高了与雄激素受体N-末端结构域结合的雷拉尼汀化合物的功效。
DOI：
10.1038/s42003-021-01927-3
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发表时间：
2021-03-22
影响因子：
5.9
通讯作者：
Sadar MD
中科院分区：
文献类型：
--
作者：
Leung JK;Imamura Y;Kato M;Wang J;Mawji NR;Sadar MD
致死性去势抵抗性前列腺癌（CRPC）的治疗是一个未满足的医疗需求。CRPC和对激素疗法的抗性的一种潜在机制是雄激素受体（AR-V）的组成型活性剪接变体（一种或多种）的表达，其缺乏其C末端配体结合结构域。AR-V和全长AR的转录活性存在于其N-末端结构域（NTD）。Ralaniten是唯一一种被证明能结合AR NTD的药物，它在1期试验中显示出了有效性。肽基脯氨酰异构酶Pin 1在前列腺癌中经常过表达。在这里，我们表明Pin 1与AR NTD相互作用。Pin 1表达或其活性的抑制选择性地降低了全长AR和AR-V7的转录活性。Pin 1抑制剂与雷拉尼丁的组合促进细胞周期停滞，并且与单独的单药治疗相比，在体内对CRPC异种移植物具有改善的抗肿瘤活性。这些发现支持了将Pin 1抑制剂与ralaniten联合治疗CRPC的基本原理。Leung等人发现肽基脯氨酰异构酶Pin 1靶向雄激素受体（AR）的固有无序N-末端结构域。他们表明，将Pin 1抑制与结合AR N端结构域的ralaniten化合物结合，增强了异种移植物中去势抵抗性前列腺癌的抗肿瘤活性，表明了治疗潜力。
Therapies for lethal castration-resistant prostate cancer (CRPC) are an unmet medical need. One mechanism underlying CRPC and resistance to hormonal therapies is the expression of constitutively active splice variant(s) of androgen receptor (AR-Vs) that lack its C-terminus ligand-binding domain. Transcriptional activities of AR-Vs and full-length AR reside in its N-terminal domain (NTD). Ralaniten is the only drug proven to bind AR NTD, and it showed promise of efficacy in Phase 1 trials. The peptidyl-prolyl isomerase Pin1 is frequently overexpressed in prostate cancer. Here we show that Pin1 interacted with AR NTD. The inhibition of Pin1 expression or its activity selectively reduced the transcriptional activities of full-length AR and AR-V7. Combination of Pin1 inhibitor with ralaniten promoted cell cycle arrest and had improved antitumor activity against CRPC xenografts in vivo compared to individual monotherapies. These findings support the rationale for therapy that combines a Pin1 inhibitor with ralaniten for treating CRPC. Leung et al. find that the peptidyl-prolyl isomerase Pin1 targets the intrinsically disordered N-terminal domain of the androgen receptor (AR). They show that combining Pin1 inhibition with ralaniten compounds that bind to the AR N-terminal domain has enhanced antitumor activity on castration-resistant prostate cancer in xenografts, suggesting therapeutic potential.
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影响因子：
16
作者：
Lee TH;Chen CH;Suizu F;Huang P;Schiene-Fischer C;Daum S;Zhang YJ;Goate A;Chen RH;Zhou XZ;Lu KP
通讯作者：
Lu KP
影响因子：
4.1
作者：
Chen, H;Juchau, MR
通讯作者：
Juchau, MR
影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J