Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia. Issue 6 (18th June 2020)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Cell chemical biology. Volume 27:Issue 6(2020)
• Page Start: 678
• Page End: 697.e13
• Publication Date: 2020-06-18
• Subjects: NOTCH1 -- NOTCH1 mutation -- PEST mutation -- T cell acute lymphoblastic leukemia (T-ALL) -- mantle cell lymphoma (MCL) -- SERCA -- thapsigargin -- CAD204520 -- P-type ATPases screening -- crystal structure; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2020.04.002
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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 Ca 2+ 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). Graphical Abstract: Highlights: Identification of CAD204520, a highly selective SERCA inhibitor Crystal structure of CAD204520 in complex with SERCA CAD204520 inhibits HD and PEST NOTCH1 mutations in lymphoid malignancies SERCA inhibition can be achieved in vivo without cardiac toxicity Abstract : 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.