On-target drug delivery remains a challenge in cancer precision medicine; it is difficult to deliver a targeted therapy to cancer cells without incurring toxicity to normal tissues. The SERCA (sarco-endoplasmic reticulum Ca²⁺ ATPase) inhibitor thapsigargin inhibits mutant NOTCH1 receptors compared with wild type in T cell acute lymphoblastic leukemia (T-ALL), but its administration is predicted to be toxic in humans. Leveraging the addiction of ALL to folic acid, we conjugated folate to an alcohol derivative of thapsigargin via a cleavable ester linkage. JQ-FT is recognized by folate receptors on the plasma membrane and delivered into leukemia cells as a potent antileukemic agent. In mechanistic and translational models of T-ALL, we demonstrate NOTCH1 inhibition in vitro and in vivo. These proof-of-concept studies support the further optimization of this first-in-class NOTCH1 inhibitor with dual selectivity: leukemia over normal cells and NOTCH1 mutants over wild-type receptors. Furthermore, tumor-specific disruption of Notch signaling may overcome legitimate concerns associated with the tumor suppressor function of nontargeted Notch pathway inhibitors.

在癌症精密医学中，按目标给药仍然是一个挑战。在不对正常组织产生毒性的情况下，很难对癌细胞进行靶向治疗。SERCA（肌内质网Ca ²⁺与野生型相比，ATP酶抑制剂thapsigargin在T细胞急性淋巴细胞白血病（T-ALL）中能抑制突变的NOTCH1受体，但据预测对人的使用是有毒的。利用ALL对叶酸的成瘾作用，我们通过可裂解的酯键将叶酸与thapsigargin的醇衍生物缀合。JQ-FT被质膜上的叶酸受体识别，并作为有效的抗白血病药物被传递到白血病细胞中。在T-ALL的机制和翻译模型中，我们证明了NOTCH1在体外和体内的抑制作用。这些概念验证研究支持这种具有双重选择性的一流NOTCH1抑制剂的进一步优化：对正常细胞的白血病和对野生型受体的NOTCH1突变。此外，