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
University of Parma, Department of Medicine and Surgery, Parma 43126, Italy.
University of Perugia, Department of Medicine, Hematology and Clinical Immunology, Perugia 06123, Italy.
Cell Chem Biol. 2020 Jun 18;27(6):678-697.e13. doi: 10.1016/j.chembiol.2020.04.002. Epub 2020 May 7.
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 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).
将肌浆/内质网钙ATP酶（SERCA）鉴定为调节Notch依赖性癌症中功能获得性NOTCH1突变的靶点，这推动了此类化合物用于癌症治疗的研发。尽管存在与SERCA抑制相关的固有毒性挑战，但我们鉴定出了CAD204520，与SERCA抑制剂毒胡萝卜素相比，它是一种具有更好类药性质且脱靶钙毒性降低的小分子。在这项工作中，我们描述了CAD204520的性质和复杂结构，并表明CAD204520在T细胞急性淋巴细胞白血病（T-ALL）和套细胞淋巴瘤（MCL）中优先靶向突变型而非野生型NOTCH1蛋白。在SERCA抑制剂中，CAD204520独特之处在于，它在T-ALL异种移植模型中抑制NOTCH1突变的白血病细胞，而不会引起心脏毒性。这项研究支持了SERCA抑制剂用于Notch依赖性癌症的研发，并将其应用扩展到NOTCH1的PEST降解结构域存在孤立突变的病例，如MCL或慢性淋巴细胞白血病（CLL）。
