Kirsten rat sarcoma virus (KRAS) is a frequently mutated oncogene in human cancer. Targeting KRAS function is a high priority for cancer drug development, and in recent years, drugs that inhibit the KRAS glycine 12–to–cysteine (G12C) mutation have been developed. However, additional KRAS tumor mutations occur with high prevalence, and there are currently no drugs available to inhibit them. Popow et al. designed a strategy to target the remaining oncogenic KRAS mutations by developing drugs called bifunctional proteolysis targeting chimera (PROTAC) degraders (see the Perspective by Cox and Der). Starting from noncovalent ligands for KRAS and the E3 ligase von Hippel-Lindau (VHL), chemical optimization guided by co-crystal structures of KRAS:PROTAC:VHL ternary complexes led to a small molecule that selectively degraded 13 of 17 of the most common mutants. KRAS degradation was more efficacious than inhibition and induced tumor regression in experimental models. —Priscilla N. Kelly
Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.
Kirsten大鼠肉瘤病毒（KRAS）是人类癌症中频繁突变的致癌基因。靶向KRAS功能是癌症药物开发的重中之重，近年来，已开发出抑制KRAS甘氨酸12至半胱氨酸（G12C）突变的药物。然而，其他KRAS肿瘤突变发生率很高，目前尚无药物可抑制它们。Popow等人设计了一种策略，通过开发称为双功能蛋白水解靶向嵌合体（PROTAC）降解剂的药物来靶向剩余的致癌KRAS突变（参见Cox和Der的观点文章）。从KRAS和E3连接酶von Hippel-Lindau（VHL）的非共价配体开始，通过KRAS:PROTAC:VHL三元复合物的共晶结构指导化学优化，得到了一种小分子，能选择性降解17种最常见突变中的13种。KRAS降解比抑制更有效，并在实验模型中诱导肿瘤消退。—Priscilla N. Kelly
Kirsten大鼠肉瘤病毒致癌基因同源物（KRAS）蛋白的突变在癌症中非常普遍。然而，除了将第12位的甘氨酸替换为半胱氨酸（G12C）——这通过共价抑制剂在临床上已有药物治疗——之外，针对致癌KRAS等位基因的小分子概念仍然难以捉摸。在三元复合物的生物物理和结构研究指导下，我们设计了一种异双功能小分子，能有效降解17种最常见致癌KRAS等位基因中的13种。与抑制相比，KRAS降解在广泛的KRAS突变细胞系中导致更深远和持续的途径调节，杀死癌细胞，同时保留没有遗传KRAS异常的模型。致癌KRAS的药理降解是耐受的，并在体内导致肿瘤消退。总之，这些发现揭示了用小分子降解剂处理KRAS驱动癌症的新途径。
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