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Discovery of a ZIP7 inhibitor from a Notch pathway screen.
Nolin, Erin; Gans, Sara; Llamas, Luis; Bandyopadhyay, Somnath; Brittain, Scott M; Bernasconi-Elias, Paula; Carter, Kyle P; Loureiro, Joseph J; Thomas, Jason R; Schirle, Markus; Yang, Yi; Guo, Ning; Roma, Guglielmo; Schuierer, Sven; Beibel, Martin; Lindeman, Alicia; Sigoillot, Frederic; Chen, Amy; Xie, Kevin X; Ho, Samuel; Reece-Hoyes, John; Weihofen, Wilhelm A; Tyskiewicz, Kayla; Hoepfner, Dominic; McDonald, Richard I; Guthrie, Nicolette; Dogra, Abhishek; Guo, Haibing; Shao, Jian; Ding, Jian; Canham, Stephen M; Boynton, Geoff; George, Elizabeth L; Kang, Zhao B; Antczak, Christophe; Porter, Jeffery A; Wallace, Owen; Tallarico, John A; Palmer, Amy E; Jenkins, Jeremy L; Jain, Rishi K; Bushell, Simon M; Fryer, Christy J.
Afiliación
  • Nolin E; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Gans S; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Llamas L; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Bandyopadhyay S; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Brittain SM; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Bernasconi-Elias P; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Carter KP; Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado, Boulder, CO, USA.
  • Loureiro JJ; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Thomas JR; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Schirle M; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Yang Y; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Guo N; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Roma G; Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Schuierer S; Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Beibel M; Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • Lindeman A; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Sigoillot F; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Chen A; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Xie KX; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Ho S; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Reece-Hoyes J; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Weihofen WA; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Tyskiewicz K; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Hoepfner D; Novartis Institutes for Biomedical Research, Basel, Switzerland.
  • McDonald RI; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Guthrie N; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Dogra A; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Guo H; Novartis Institutes for Biomedical Research, Shanghai, China.
  • Shao J; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Ding J; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Canham SM; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Boynton G; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • George EL; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Kang ZB; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Antczak C; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Porter JA; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Wallace O; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Tallarico JA; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Palmer AE; Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado, Boulder, CO, USA.
  • Jenkins JL; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Jain RK; Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
  • Bushell SM; Novartis Institutes for Biomedical Research, Cambridge, MA, USA. simon.bushell@novartis.com.
  • Fryer CJ; Novartis Institutes for Biomedical Research, Cambridge, MA, USA. christy.fryer@novartis.com.
Nat Chem Biol ; 15(2): 179-188, 2019 02.
Article en En | MEDLINE | ID: mdl-30643281
ABSTRACT
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas de Transporte de Catión / Receptor Notch1 / Estrés del Retículo Endoplásmico Límite: Animals / Humans Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas de Transporte de Catión / Receptor Notch1 / Estrés del Retículo Endoplásmico Límite: Animals / Humans Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos