A Cell Type Selective YM155 Prodrug Targets Receptor-Interacting Protein Kinase 2 to Induce Brain Cancer Cell Death.
A Cell Type Selective YM155 Prodrug Targets Receptor-Interacting Protein Kinase 2 to Induce Brain Cancer Cell Death.
复制标题
细胞类型选择性 YM155 前药以受体相互作用蛋白激酶 2 为靶点，诱导脑癌细胞死亡。
DOI：
10.1021/jacs.2c11715
复制
发表时间：
2023
影响因子：
15
通讯作者：
Lairson,LukeL
中科院分区：
文献类型：
--
作者：
West,ThomasJ;Bi,Junfeng;Martínez-Peña,Francisco;Curtis,EllisJ;Gazaniga,NathaliaR;Mischel,PaulS;Lairson,LukeL
胶质母细胞瘤（GBM）是最常见和最具侵袭性的原发性中枢神经系统（CNS）恶性肿瘤。YM 155是一种高效的广谱抗癌药物，其来源于存活素表达的功能性抑制剂的表型筛选，但其相关的生物分子靶标仍然未知。据推测，由于缺乏细胞类型选择性，YM 155在临床上存在耐受性问题。基于其与GBM选择性前药RIPGBM的结构相似性，在这里，我们报告了YM 155的前药形式的设计、合成和表征，称为aYM 155。aYM 155对广泛的患者来源的GBM癌症干细胞样细胞（IC 50 = 0.7-10 nM）以及EGFR扩增和EGFR变体III表达（EGFRvIII）细胞系（IC 50 = 3.8-36 nM）显示出有效的细胞杀伤活性，并以细胞类型依赖性方式被激活。基于质谱的分析表明，转化细胞类型与非转化细胞类型中前药活化的相对速率导致细胞类型选择性增强。前药策略还促进转运到脑中（脑-血浆比，aYM 155 = 0.56; YM 155 = BLQ）。此外，我们确定YM 155的生存素抑制和凋亡诱导活性涉及其与受体相互作用蛋白激酶2（RIPK 2）的相互作用。在原位颅内GBM异种移植模型中，YM 155前药显著抑制体内脑肿瘤生长，这与基于细胞类型选择性存活素的药效学效应相关。
Glioblastoma (GBM) is the most prevalent and aggressive primary central nervous system (CNS) malignancy. YM155 is a highly potent broad-spectrum anti-cancer drug that was derived from a phenotypic screen for functional inhibitors of survivin expression, but for which the relevant biomolecular target remains unknown. Presumably as a result of its lack of cell-type selectivity, YM155 has suffered from tolerability issues in the clinic. Based on its structural similarity to the GBM-selective prodrug RIPGBM, here, we report the design, synthesis, and characterization of a prodrug form of YM155, termed aYM155. aYM155 displays potent cell killing activity against a broad panel of patient-derived GBM cancer stem-like cells (IC50= 0.7–10 nM), as well as EGFR-amplified and EGFR variant III-expressing (EGFRvIII) cell lines (IC50= 3.8–36 nM), and becomes activated in a cell-type-dependent manner. Mass spectrometry-based analysis indicates that enhanced cell-type selectivity results from relative rates of prodrug activation in transformed versus non-transformed cell types. The prodrug strategy also facilitates transport into the brain (brain-to-plasma ratio, aYM155 = 0.56; YM155 = BLQ). In addition, we determine that the survivin-suppressing and apoptosis-inducing activities of YM155 involve its interaction with receptor-interacting protein kinase 2 (RIPK2). In an orthotopic intracranial GBM xenograft model, aYM155 prodrug significantly inhibits brain tumor growthin vivo, which correlates with cell-type selective survivin-based pharmacodynamic effects.