KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, KRASG12C can be targeted by small-molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound. Our lead degrader successfully engaged CRBN in cells, bound KRASG12Cin vitro, induced CRBN/KRASG12C dimerization, and degraded GFP-KRASG12C in reporter cells in a CRBN-dependent manner. However, it failed to degrade endogenous KRASG12C in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively poly-ubiquitinate endogenous KRASG12C underlies the lack of activity. We discuss challenges for achieving targeted KRASG12C degradation and proposed several possible solutions which may lead to efficient degradation of endogenous KRASG12C.

中文翻译：

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探索致癌的KRASG12C的目标降解策略。

KRAS是在胰腺癌，结肠直肠癌和肺癌中发现的最常见的突变癌基因。尽管确定具有KRAS突变的癌症的靶向疗法一直具有挑战性，但KRASG12C可以被与半胱氨酸12（C12）形成共价键的小分子抑制剂靶向。在这里，我们设计了一个C12定向共价降解分子（PROTAC）库，并对其进行了严格的评估，以快速鉴定先导化合物。我们的主要降解剂成功地将CRBN结合到细胞中，并在体外与KRASG12C结合，诱导CRBN / KRASG12C二聚化，并以依赖CRBN的方式降解了报告细胞中的GFP-KRASG12C。但是，它未能降解胰腺和肺癌细胞中的内源性KRASG12C。我们的数据表明，铅降解剂不能有效地多聚泛素化内源性KRASG12C，这是缺乏活性的基础。我们讨论了实现目标KRASG12C降解的挑战，并提出了几种可能导致内源性KRASG12C有效降解的解决方案。