Most small-molecule drugs that target oncogenic Kirsten rat sarcoma virus (KRAS) mutants rely on interactions with variant-specific amino acid residues. However, a wide range of KRAS mutations are prevalent in human cancers, and undruggable variants pose a great challenge to the clinical treatment of KRAS-mutant tumors. In a paper published in Science, Popow et al. address this issue by designing a proteolysis-targeting chimera (PROTAC) that degrades a broad spectrum of KRAS variants.

A structure-based design approach yielded a potent KRAS-selective degrader that targets the switch II pocket, which is conserved across KRAS variants. The researchers coupled a previously used ligand to a linker together with a binding motif for the Von Hippel–Lindau (VHL) E3 ligase. Lead compound optimization improved stability and engagement with intracellular VHL, resulting in a PROTAC that efficiently degraded 13 out of 17 KRAS mutant variants in vitro. Unbiased mass spectrometry proteomics showed >50% protein depletion and detected only KRAS, indicating that the PROTAC is highly selective for KRAS. Pan-KRAS degradation suppressed oncogenic MAPK signaling and inhibited proliferation in cancer cell lines driven by diverse KRAS mutants. KRAS degradation was more than 10-fold more potent than KRAS inhibition. An in vivo optimized compound, called ACB13, caused regression of KRAS mutant tumors in mice.

大多数靶向致癌 Kirsten 大鼠肉瘤病毒 （KRAS） 突变体的小分子药物依赖于与变体特异性氨基酸残基的相互作用。然而，KRAS 突变在人类癌症中普遍存在，不可成药的变异对 KRAS 突变肿瘤的临床治疗构成巨大挑战。在发表在《科学》杂志上的一篇论文中，Popow 等人通过设计一种蛋白水解靶向嵌合体 （PROTAC） 来降解广泛的 KRAS 变体来解决这个问题。

基于结构的设计方法产生了一种有效的 KRAS 选择性降解剂，该降解剂靶向开关 II 口袋，该降解剂在 KRAS 变体中是保守的。研究人员将先前使用的配体与接头与 Von Hippel-Lindau （VHL） E3 连接酶的结合基序偶联。先导化合物优化提高了稳定性和与细胞内 VHL 的结合，从而使 PROTAC 在体外有效降解了 17 种 KRAS 突变变体中的 13 种。无偏倚质谱蛋白质组学显示 >50% 蛋白质耗竭，仅检测到 KRAS，表明 PROTAC 对 KRAS 具有高度选择性。Pan-KRAS 降解抑制了不同 KRAS 突变体驱动的致癌 MAPK 信号传导并抑制了癌细胞系的增殖。KRAS 降解比 KRAS 抑制强 10 倍以上。一种称为 ACB13 的体内优化化合物导致小鼠 KRAS 突变肿瘤消退。