Exploring Targeted Degradation Strategy for Oncogenic KRASG12C
Exploring Targeted Degradation Strategy for Oncogenic KRASG12C
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DOI：
10.1016/j.chembiol.2019.12.006
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发表时间：
2020-01-16
影响因子：
8.6
通讯作者：
Gray, Nathanael S.
中科院分区：
文献类型：
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作者：
Zeng, Mei;Xiong, Yuan;Gray, Nathanael S.
KRAS是在胰腺癌、结直肠癌和肺癌中发现的最常见的突变癌基因。尽管确定针对KRAS突变的癌症的靶向治疗一直具有挑战性，但KRAS（G12C）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导向的共价降解分子（PROTACs）文库，并对它们进行了严格的评估过程，以快速识别先导化合物。我们的铅降解剂成功地在细胞中结合CRBN，在体外结合KRAS(G12C)，诱导CRBN/KRAS（G12C）二聚化，并以CRBN依赖的方式在报告细胞中降解GFPKRAS（G12C）。然而，它不能降解胰腺癌和肺癌细胞中的内源性KRAS（G12C）。我们的数据表明，铅降解物无法有效地多泛素化内源性KRAS（G12C）是缺乏活性的原因。我们讨论了实现靶向KRAS（G12C）降解的挑战，并提出了几种可能导致内源性KRAS（G12C）有效降解的解决方案。
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, KRAS(G12C) 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 KRAS(G12C) in vitro, induced CRBN/KRAS(G12C) dimerization, and degraded GFPKRAS(G12C) in reporter cells in a CRBN-dependent manner. However, it failed to degrade endogenous KRAS(G12C) in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively poly-ubiquitinate endogenous KRAS(G12C) underlies the lack of activity. We discuss challenges for achieving targeted KRAS(G12C) degradation and proposed several possible solutions which may lead to efficient degradation of endogenous KRAS(G12C).