RAS proteins are the most frequently mutated in cancer, yet they have proved extremely difficult to target for drug discovery, largely because interfering with the interaction of RAS with its downstream effectors comes up against the challenge of protein-protein interactions (PPIs). Sequence-defined synthetic oligomers could combine the precision and customisability of synthetic molecules with the size requirements to address entire PPI surfaces. We have adapted the phosphoramidite chemistry of oligonucleotide synthesis to produce a library of nearly one million non-nucleosidic oligophosphoester sequences (phosphoestamers) composed of units taken from synthetic supramolecular chemistry, and used a fluorescent-activated bead sorting (FABS) process to select those that inhibit the interaction between KRAS^G12D (the most prevalent, and undrugged, RAS mutant) and RAF, a downstream effector of RAS that drives cell proliferation. Hits were identified using tandem mass spectrometry, and orthogonal validation showed effective inhibition of KRAS^G12D with IC50 values as low as 25 nM, and excellent selectivity over the wild type form. These findings have the potential to lead to new drugs that target mutant RAS-driven cancers, and provide proof-of-principle for the phosphoestamer chemical platform against PPIs in general – opening up new possibilities in neurodegenerative disease, viral infection, and many more conditions.

中文翻译：

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用于选择性抑制 KRASG12D/RAF1 相互作用的序列定义的磷酸化聚体


RAS 蛋白是癌症中突变最频繁的蛋白，但事实证明，它们极难成为药物发现的靶标，这主要是因为干扰 RAS 与其下游效应子的相互作用会面临蛋白质-蛋白质相互作用 （PPI） 的挑战。序列定义的合成低聚物可以将合成分子的精度和可定制性与尺寸要求相结合，以满足整个 PPI 表面的要求。我们调整了寡核苷酸合成的亚磷酰胺化学，以产生一个包含近 100 万个非核苷寡磷酸酯序列（磷酸酯）的库，该序列由来自合成超分子化学的单元组成，并使用荧光激活珠分选 （FABS） 工艺来选择那些抑制 KRAS^G12D 之间相互作用的序列（最普遍且未上药的 RAS 突变体）和 RAF，RAF 是驱动细胞增殖的 RAS 下游效应子。使用串联质谱法鉴定命中，正交验证显示对 KRAS^G12D 有效抑制，IC50 值低至 25 nM，并且对野生型具有优异的选择性。这些发现有可能导致针对突变 RAS 驱动癌症的新药，并为针对 PPI 的磷酸化化学平台提供原理验证——为神经退行性疾病、病毒感染和更多疾病开辟了新的可能性。