6yaa

Structure of the (SR) Ca2+-ATPase bound to the inhibitor compound CAD204520 and TNP-ATP

spinqualitylabelsall models 6yaa, resolution 3.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.4Å Ligands: 128, K, OHW Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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). Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia.,Marchesini M, Gherli A, Montanaro A, Patrizi L, Sorrentino C, Pagliaro L, Rompietti C, Kitara S, Heit S, Olesen CE, Moller JV, 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 AM, Sportoletti P, Bublitz M, Dalby-Brown W, Roti G Cell Chem Biol. 2020 Apr 15. pii: S2451-9456(20)30116-1. doi:, 10.1016/j.chembiol.2020.04.002. PMID:32386594 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also ATPase 3D structures

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