Blockade of oncogenic NOTCH1 with the SERCA inhibitor CAD204520 in T cell acute lymphoblastic leukemia

Journal article

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).

Authors: Marchesini, M; Gherli, A; Montanaro, A; Patrizi, L; Sorrentino, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cell Chemical Biology
• Volume: 27
• Issue: 6
• Pages: 678-697
• Publication date: 2020-05-07
• Acceptance date: 2020-03-31
• DOI: 10.1016/j.chembiol.2020.04.002
• EISSN: 2451-9448
• ISSN: 2451-9456
• Pmid: 32386594
• Language: English
• Keywords: FFR