Molecular brush-conjugated antisense oligonucleotide as a pan-KRAS depletion agent

项目摘要/摘要 突变形式的KRAS是人类肿瘤的关键驱动因素，但对治疗仍部分无效 干预。经过三十多年的研究，只有一种抑制剂(索托拉西布)针对单一的 突变(KRASG12C)已经上市。开发小分子KRAS抑制剂的难点 提高了针对癌基因的替代方法的重要性。一种这样的策略 涉及治疗性核酸，这使得耗尽难以处理的靶蛋白成为可能 常规药物模式。我们已经开发出一种新形式的核酸疗法，称为 布鲁塞尔™结合物，大大增强了反义寡核苷酸的抗肿瘤活性 通过提高体内稳定性，加速细胞摄取，改善血浆药代动力学和 肿瘤堆积，允许使用比传统方法低得多的剂量。 这种结合物还通过以下方式抑制几乎所有与传统核酸药物有关的副作用 减少不必要的核酸-蛋白质相互作用。这项提议的目标是为 将这项技术转化为临床应用。在第一阶段，我们会优化 布鲁斯希尔德™结合物，并使用一组非小细胞肺细胞和 小鼠异种移植模型。在达到设定的数量里程碑时，我们将对共轭进行 更相关的动物模型(原位和患者来源的异种移植模型)，并执行耐受性 在小鼠和猴子身上的药代动力学研究(第二阶段)。这些研究将使我们能够继续进行 在项目结束时提交IND文件。

Project Summary/Abstract Mutant forms of KRAS are a key driver in human tumors but remain partially refractory to therapeutic intervention. After over three decades of research, only a single inhibitor (sotorasib) targeting a single mutation (KRASG12C) have reached market. The difficulty for developing small molecule KRAS inhibitors has heightened the importance of alternative methods targeting the oncogene. One such strategy involves therapeutic nucleic acids, which make it possible to deplete target proteins that are intractable to conventional drug modalities. We have developed a novel form of nucleic acid therapeutics, termed Brushield™ conjugate, which substantially enhances the antitumor activity of antisense oligonucleotides by elevating in vivo stability, accelerating cellular uptake, and improving plasma pharmacokinetics and tumor accumulation, allowing for a much lower dosage to be used compared to conventional methods. The conjugate also suppresses nearly all side effects associated with traditional nucleic acid drugs by reducing unwanted nucleic acid-protein interactions. The goal of this proposal is to lay the groundwork for translating the technology towards the clinic. In Phase I, we will optimize the structure of the Brushield™ conjugate, and enhance current indication using a panel of non-small cell lung cells and mouse xenograft models. Upon reaching set quantitative milestones, we will subject the conjugate to more relevant animal models (orthotopic and patient-derived xenograft models), and perform tolerability and pharmacokinetic studies in mice and monkeys (Phase II). These studies will allow us to pursue an IND filing at the end of the project.