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).

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)。