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Discovery of a ZIP7 inhibitor from a Notch pathway screen.
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2019-01-14 , DOI: 10.1038/s41589-018-0200-7 Erin Nolin 1 , Sara Gans 1 , Luis Llamas 1 , Somnath Bandyopadhyay 1 , Scott M Brittain 1 , Paula Bernasconi-Elias 1 , Kyle P Carter 2 , Joseph J Loureiro 1 , Jason R Thomas 1 , Markus Schirle 1 , Yi Yang 1 , Ning Guo 1 , Guglielmo Roma 3 , Sven Schuierer 3 , Martin Beibel 3 , Alicia Lindeman 1 , Frederic Sigoillot 1 , Amy Chen 1 , Kevin X Xie 1 , Samuel Ho 1 , John Reece-Hoyes 1 , Wilhelm A Weihofen 1 , Kayla Tyskiewicz 1 , Dominic Hoepfner 3 , Richard I McDonald 1 , Nicolette Guthrie 1 , Abhishek Dogra 1 , Haibing Guo 4 , Jian Shao 1 , Jian Ding 1 , Stephen M Canham 1 , Geoff Boynton 1 , Elizabeth L George 1 , Zhao B Kang 1 , Christophe Antczak 1 , Jeffery A Porter 1 , Owen Wallace 1 , John A Tallarico 1 , Amy E Palmer 2 , Jeremy L Jenkins 1 , Rishi K Jain 1 , Simon M Bushell 1 , Christy J Fryer 1
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2019-01-14 , DOI: 10.1038/s41589-018-0200-7 Erin Nolin 1 , Sara Gans 1 , Luis Llamas 1 , Somnath Bandyopadhyay 1 , Scott M Brittain 1 , Paula Bernasconi-Elias 1 , Kyle P Carter 2 , Joseph J Loureiro 1 , Jason R Thomas 1 , Markus Schirle 1 , Yi Yang 1 , Ning Guo 1 , Guglielmo Roma 3 , Sven Schuierer 3 , Martin Beibel 3 , Alicia Lindeman 1 , Frederic Sigoillot 1 , Amy Chen 1 , Kevin X Xie 1 , Samuel Ho 1 , John Reece-Hoyes 1 , Wilhelm A Weihofen 1 , Kayla Tyskiewicz 1 , Dominic Hoepfner 3 , Richard I McDonald 1 , Nicolette Guthrie 1 , Abhishek Dogra 1 , Haibing Guo 4 , Jian Shao 1 , Jian Ding 1 , Stephen M Canham 1 , Geoff Boynton 1 , Elizabeth L George 1 , Zhao B Kang 1 , Christophe Antczak 1 , Jeffery A Porter 1 , Owen Wallace 1 , John A Tallarico 1 , Amy E Palmer 2 , Jeremy L Jenkins 1 , Rishi K Jain 1 , Simon M Bushell 1 , Christy J Fryer 1
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The identification of activating mutations in NOTCH1 in 50% of T cell acute lymphoblastic leukemia has generated interest in elucidating how these mutations contribute to oncogenic transformation and in targeting the pathway. A phenotypic screen identified compounds that interfere with trafficking of Notch and induce apoptosis via an endoplasmic reticulum (ER) stress mechanism. Target identification approaches revealed a role for SLC39A7 (ZIP7), a zinc transport family member, in governing Notch trafficking and signaling. Generation and sequencing of a compound-resistant cell line identified a V430E mutation in ZIP7 that confers transferable resistance to the compound NVS-ZP7-4. NVS-ZP7-4 altered zinc in the ER, and an analog of the compound photoaffinity labeled ZIP7 in cells, suggesting a direct interaction between the compound and ZIP7. NVS-ZP7-4 is the first reported chemical tool to probe the impact of modulating ER zinc levels and investigate ZIP7 as a novel druggable node in the Notch pathway.
中文翻译：
从Notch途径筛选中发现ZIP7抑制剂。
在50％的T细胞急性淋巴细胞白血病中，NOTCH1的激活突变的鉴定引起了人们的兴趣，以阐明这些突变如何促进致癌转化和靶向该途径。表型筛选确定了干扰Notch转运并通过内质网（ER）应激机制诱导凋亡的化合物。目标识别方法揭示了锌运输家族成员SLC39A7（ZIP7）在调控Notch交易和信号传导中的作用。化合物抗性细胞系的产生和测序鉴定出ZIP7中的V430E突变，赋予了对化合物NVS-ZP7-4的可转移抗性。NVS-ZP7-4改变了ER中的锌，并改变了化合物在细胞中标记为ZIP7的光亲和力的类似物，表明该化合物与ZIP7之间存在直接的相互作用。
更新日期：2019-01-25
中文翻译：
从Notch途径筛选中发现ZIP7抑制剂。
在50％的T细胞急性淋巴细胞白血病中，NOTCH1的激活突变的鉴定引起了人们的兴趣，以阐明这些突变如何促进致癌转化和靶向该途径。表型筛选确定了干扰Notch转运并通过内质网（ER）应激机制诱导凋亡的化合物。目标识别方法揭示了锌运输家族成员SLC39A7（ZIP7）在调控Notch交易和信号传导中的作用。化合物抗性细胞系的产生和测序鉴定出ZIP7中的V430E突变，赋予了对化合物NVS-ZP7-4的可转移抗性。NVS-ZP7-4改变了ER中的锌，并改变了化合物在细胞中标记为ZIP7的光亲和力的类似物，表明该化合物与ZIP7之间存在直接的相互作用。
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