2. Academic Validation
  3. Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia

Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia

  • Cell Chem Biol. 2020 Jun 18;27(6):678-697.e13. doi: 10.1016/j.chembiol.2020.04.002.
Matteo Marchesini 1,  Andrea Gherli 1,  Anna Montanaro 1,  Laura Patrizi 2,  Claudia Sorrentino 1,  Luca Pagliaro 1,  Chiara Rompietti 2,  Samuel Kitara 3,  Sabine Heit 4,  Claus E Olesen 5,  Jesper V Møller 5,  Monia Savi 6,  Leonardo Bocchi 6,  Rocchina Vilella 6,  Federica Rizzi 7,  Marilena Baglione 1,  Giorgia Rastelli 1,  Caterina Loiacono 1,  Roberta La Starza 2,  Cristina Mecucci 2,  Kimberly Stegmaier 8,  Franco Aversa 1,  Donatella Stilli 6,  Anne-Marie Lund Winther 9,  Paolo Sportoletti 2,  Maike Bublitz 4,  William Dalby-Brown 9,  Giovanni Roti 10
Affiliations

Affiliations

  • 1 University of Parma, Department of Medicine and Surgery, Parma 43126, Italy.
  • 2 University of Perugia, Department of Medicine, Hematology and Clinical Immunology, Perugia 06123, Italy.
  • 3 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 4 University of Oxford, Department of Biochemistry, Oxford OX1 3QU, UK.
  • 5 Aarhus University, Department of Biomedicine, 8000 Aarhus C, Denmark.
  • 6 University of Parma, Department of Chemistry, Life Sciences and Environmental Sustainability, Parma 43124, Italy.
  • 7 University of Parma, Department of Medicine and Surgery, Parma 43126, Italy; INBB - Biostructures and Biosystems National Institute, Rome 00136, Italy.
  • 8 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute, Cambridge, MA 02142, USA.
  • 9 Cado Biotechnology IvS, Copenhagen, Denmark.
  • 10 University of Parma, Department of Medicine and Surgery, Parma 43126, Italy. Electronic address: giovanni.roti@unipr.it.
PMID: 32386594 DOI: 10.1016/j.chembiol.2020.04.002
Abstract

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).

Keywords

CAD204520; NOTCH1; NOTCH1 mutation; P-type ATPases screening; PEST mutation; SERCA; T cell acute lymphoblastic leukemia (T-ALL); crystal structure; mantle cell lymphoma (MCL); thapsigargin.

Figures
Products