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Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2020-05-07 , 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 1
Affiliation  

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).



中文翻译:


在 T 细胞急性淋巴细胞白血病中使用 SERCA 抑制剂 CAD204520 阻断致癌 NOTCH1。



SERCA(肌肉/内质网钙 ATP 酶)作为调节 Notch 依赖性癌症中功能获得性NOTCH1突变的靶标的鉴定,刺激了此类癌症治疗化合物的开发。尽管存在与 SERCA 抑制相关的先天毒性挑战,但我们还是鉴定出了 CAD204520,这是一种小分子,与 SERCA 抑制剂毒胡萝卜素相比,具有更好的药物样特性并降低了脱靶 Ca 2+毒性。在这项工作中,我们描述了 CAD204520 的特性和复杂结构,并表明 CAD204520 优先针对 T 细胞急性淋巴细胞白血病 (T-ALL) 和套细胞淋巴瘤 (MCL) 中的突变型 NOTCH1 蛋白。在 SERCA 抑制剂中,CAD204520 是独一无二的,它可以抑制 T-ALL 异种移植模型中的NOTCH1突变白血病细胞,而不会引起心脏毒性。这项研究支持开发针对 Notch 依赖性癌症的 SERCA 抑制剂,并将其应用扩展到NOTCH1 PEST 降解结构域中存在孤立突变的病例,例如 MCL 或慢性淋巴细胞白血病 (CLL)。

更新日期:2020-06-18
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