Despite nearly four decades of effort, broad inhibition of oncogenic RAS using small-molecule approaches has proven to be a major challenge. Here we describe the development of a pan-RAS biologic inhibitor composed of the RAS-RAP1–specific endopeptidase fused to the protein delivery machinery of diphtheria toxin. We show that this engineered chimeric toxin irreversibly cleaves and inactivates intracellular RAS at low picomolar concentrations terminating downstream signaling in receptor-bearing cells. Furthermore, we demonstrate in vivo target engagement and reduction of tumor burden in three mouse xenograft models driven by either wild-type or mutant RAS. Intracellular delivery of a potent anti-RAS biologic through a receptor-mediated mechanism represents a promising approach to developing RAS therapeutics against a broad array of cancers.

尽管经过近四年的努力，使用小分子方法广泛抑制致癌 RAS 已被证明是一项重大挑战。在这里，我们描述了一种由 RAS-RAP1 特异性内肽酶与白喉毒素的蛋白质传递机制融合而成的泛 RAS 生物抑制剂的开发。我们表明，这种工程化的嵌合毒素在低皮摩尔浓度下不可逆地裂解和灭活细胞内 RAS，从而终止携带受体的细胞中的下游信号传导。此外，我们在野生型或突变型RAS驱动的三种小鼠异种移植模型中证明了体内靶点参与和肿瘤负荷的减少. 通过受体介导的机制在细胞内递送有效的抗 RAS 生物制剂代表了一种有前途的方法来开发针对多种癌症的 RAS 疗法。