Blockade of oncogenic NOTCH1 with the SERCA inhibitor CAD204520 in T cell acute lymphoblastic leukemia
| Autor: | Maike Bublitz, William Dalby-Brown, Franco Aversa, Paolo Sportoletti, Anne-Marie Lund Winther, Marilena Baglione, Giorgia Rastelli, Chiara Rompietti, Rocchina Vilella, Donatella Stilli, Caterina Loiacono, Federica Rizzi, Samuel Kitara, Luca Pagliaro, Giovanni Roti, Andrea Gherli, Claus Olesen, Anna Montanaro, Roberta La Starza, Monia Savi, Matteo Marchesini, Leonardo Bocchi, Cristina Mecucci, Laura Patrizi, Sabine Heit, Claudia Sorrentino, Jesper V. Møller, Kimberly Stegmaier |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
CAD204520 Chronic lymphocytic leukemia Clinical Biochemistry Mice SCID Precursor T-Cell Lymphoblastic Leukemia-Lymphoma 01 natural sciences Biochemistry Enzyme Inhibitors/chemical synthesis Cell Proliferation/drug effects chemistry.chemical_compound Mice NOTCH1 Mice Inbred NOD Signal Transduction/drug effects hemic and lymphatic diseases Drug Discovery NOTCH1 mutation Enzyme Inhibitors Receptor Notch1 Receptor Notch1/antagonists & inhibitors Antineoplastic Agents/chemical synthesis Mice Inbred BALB C Mice Inbred ICR Molecular Structure P-type ATPases screening PEST mutation SERCA T cell acute lymphoblastic leukemia (T-ALL) crystal structure mantle cell lymphoma (MCL) thapsigargin ER STRESS RECURRENT MUTATIONS medicine.anatomical_structure Toxicity cardiovascular system Molecular Medicine Female CALCIUM PUMPS GAMMA-SECRETASE INHIBITORS Signal Transduction Thapsigargin T cell THAPSIGARGIN ANALOGS Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy Antineoplastic Agents Biology Article Neoplasms Experimental/drug therapy RETICULUM CA2+ ATPASE Cell Line Tumor medicine Animals Humans PROTON PUMP Molecular Biology Cell Proliferation Pharmacology THERAPEUTIC TARGET UNFOLDED-PROTEIN-RESPONSE 010405 organic chemistry Endoplasmic reticulum AMINO-ACID 256 Cancer Neoplasms Experimental medicine.disease 0104 chemical sciences Calcium ATPase chemistry Mutation Cancer research Drug Screening Assays Antitumor |
| Zdroj: | Cell Chem Biol Marchesini, M, Gherli, A, Montanaro, A, Patrizi, L, Sorrentino, C, Pagliaro, L, Rompietti, C, Kitara, S, Heit, S, Olesen, C E, Møller, J V, Savi, M, Bocchi, L, Vilella, R, Rizzi, F, Baglione, M, Rastelli, G, Loiacono, C, La Starza, R, Mecucci, C, Stegmaier, K, Aversa, F, Stilli, D, Lund Winther, A M, Sportoletti, P, Bublitz, M, Dalby-Brown, W & Roti, G 2020, ' Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia ', Cell Chemical Biology, vol. 27, no. 6, pp. 678-697.e13 . https://doi.org/10.1016/j.chembiol.2020.04.002 |
| DOI: | 10.1016/j.chembiol.2020.04.002 |
| Popis: | 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). Clinical translation of SERCA inhibitors has been hampered by the risk of adverse cardiac events. In this work, Marchesini and Gherli et al. identified a tolerable oral available SERCA inhibitor, CAD204520, and showed that modulation of clinically relevant NOTCH1 mutations in T cell acute lymphoblastic leukemia and mantle cell lymphoma. |
| Databáze: | OpenAIRE |
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