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Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia.
Marchesini, Matteo; Gherli, Andrea; Montanaro, Anna; Patrizi, Laura; Sorrentino, Claudia; Pagliaro, Luca; Rompietti, Chiara; Kitara, Samuel; Heit, Sabine; Olesen, Claus E; Møller, Jesper V; Savi, Monia; Bocchi, Leonardo; Vilella, Rocchina; Rizzi, Federica; Baglione, Marilena; Rastelli, Giorgia; Loiacono, Caterina; La Starza, Roberta; Mecucci, Cristina; Stegmaier, Kimberly; Aversa, Franco; Stilli, Donatella; Lund Winther, Anne-Marie; Sportoletti, Paolo; Bublitz, Maike; Dalby-Brown, William; Roti, Giovanni.
Afiliación
  • Marchesini M; University of Parma, Department of Medicine and Surgery, Parma 43126, Italy.
  • Gherli A; University of Parma, Department of Medicine and Surgery, Parma 43126, Italy.
  • Montanaro A; University of Parma, Department of Medicine and Surgery, Parma 43126, Italy.
  • Patrizi L; University of Perugia, Department of Medicine, Hematology and Clinical Immunology, Perugia 06123, Italy.
  • Sorrentino C; University of Parma, Department of Medicine and Surgery, Parma 43126, Italy.
  • Pagliaro L; University of Parma, Department of Medicine and Surgery, Parma 43126, Italy.
  • Rompietti C; University of Perugia, Department of Medicine, Hematology and Clinical Immunology, Perugia 06123, Italy.
  • Kitara S; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Heit S; University of Oxford, Department of Biochemistry, Oxford OX1 3QU, UK.
  • Olesen CE; Aarhus University, Department of Biomedicine, 8000 Aarhus C, Denmark.
  • Møller JV; Aarhus University, Department of Biomedicine, 8000 Aarhus C, Denmark.
  • Savi M; University of Parma, Department of Chemistry, Life Sciences and Environmental Sustainability, Parma 43124, Italy.
  • Bocchi L; University of Parma, Department of Chemistry, Life Sciences and Environmental Sustainability, Parma 43124, Italy.
  • Vilella R; University of Parma, Department of Chemistry, Life Sciences and Environmental Sustainability, Parma 43124, Italy.
  • Rizzi F; University of Parma, Department of Medicine and Surgery, Parma 43126, Italy; INBB - Biostructures and Biosystems National Institute, Rome 00136, Italy.
  • Baglione M; University of Parma, Department of Medicine and Surgery, Parma 43126, Italy.
  • Rastelli G; University of Parma, Department of Medicine and Surgery, Parma 43126, Italy.
  • Loiacono C; University of Parma, Department of Medicine and Surgery, Parma 43126, Italy.
  • La Starza R; University of Perugia, Department of Medicine, Hematology and Clinical Immunology, Perugia 06123, Italy.
  • Mecucci C; University of Perugia, Department of Medicine, Hematology and Clinical Immunology, Perugia 06123, Italy.
  • Stegmaier K; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute, Cambridge, MA 02142, USA.
  • Aversa F; University of Parma, Department of Medicine and Surgery, Parma 43126, Italy.
  • Stilli D; University of Parma, Department of Chemistry, Life Sciences and Environmental Sustainability, Parma 43124, Italy.
  • Lund Winther AM; Cado Biotechnology IvS, Copenhagen, Denmark.
  • Sportoletti P; University of Perugia, Department of Medicine, Hematology and Clinical Immunology, Perugia 06123, Italy.
  • Bublitz M; University of Oxford, Department of Biochemistry, Oxford OX1 3QU, UK.
  • Dalby-Brown W; Cado Biotechnology IvS, Copenhagen, Denmark.
  • Roti G; University of Parma, Department of Medicine and Surgery, Parma 43126, Italy. Electronic address: giovanni.roti@unipr.it.
Cell Chem Biol ; 27(6): 678-697.e13, 2020 06 18.
Article en En | MEDLINE | ID: mdl-32386594
The identification of SERCA (sarco/endoplasmic reticulum calcium ATPase) as a target for modulating gain-of-function NOTCH1 mutations in Notch-dependent cancers has spurred the development of this compound class for cancer therapeutics. Despite the innate toxicity challenge associated with SERCA inhibition, we identified CAD204520, a small molecule with better drug-like properties and reduced off-target Ca2+ toxicity compared with the SERCA inhibitor thapsigargin. In this work, we describe the properties and complex structure of CAD204520 and show that CAD204520 preferentially targets mutated over wild-type NOTCH1 proteins in T cell acute lymphoblastic leukemia (T-ALL) and mantle cell lymphoma (MCL). Uniquely among SERCA inhibitors, CAD204520 suppresses NOTCH1-mutated leukemic cells in a T-ALL xenografted model without causing cardiac toxicity. This study supports the development of SERCA inhibitors for Notch-dependent cancers and extends their application to cases with isolated mutations in the PEST degradation domain of NOTCH1, such as MCL or chronic lymphocytic leukemia (CLL).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores Enzimáticos / Receptor Notch1 / Leucemia-Linfoma Linfoblástico de Células T Precursoras / Antineoplásicos Límite: Animals / Female / Humans / Male Idioma: En Revista: Cell Chem Biol Año: 2020 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores Enzimáticos / Receptor Notch1 / Leucemia-Linfoma Linfoblástico de Células T Precursoras / Antineoplásicos Límite: Animals / Female / Humans / Male Idioma: En Revista: Cell Chem Biol Año: 2020 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos