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
  • 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: [email protected].
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.
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