Institute of Pharmacology, Medical University of Vienna, Vienna, 1090, Austria.
Oncol Res. 2024 Jul 17;32(8):1257-1264. doi: 10.32604/or.2024.051653. eCollection 2024.
The Kirsten rat sarcoma virus-son of sevenless 1 (KRAS-SOS1) axis drives tumor growth preferentially in pancreatic, colon, and lung cancer. Now, KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of KRAS. However, the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%, lasting for a mean period of 8 months. One approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras (PROTACs), which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of activity. Accordingly, PROTACs have been developed based on KRAS- or SOS1-directed inhibitors coupled to either von Hippel-Lindau (VHL) or Cereblon (CRBN) ligands that invoke the proteasomal degradation. Several of these PROTACs show increased activity and compared to their cognate inhibitors but their toxicity in normal tissues is not clear. The CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental animals. Resistance to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin ligase. Although highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.
Kirsten 大鼠肉瘤病毒-七肽受体 1（KRAS-SOS1）轴优先驱动胰腺、结肠和肺癌的肿瘤生长。现在，KRAS G12C 突变肿瘤可以成功地用共价阻断 KRAS 开关 II 结合口袋中半胱氨酸的抑制剂治疗。然而，其他 KRAS 突变的范围不能用治疗方法处理，并且 G12C 定向的 Sotorasib 和 Adragrasib 抑制剂的反应率仅约为 40%，平均持续时间为 8 个月。提高抑制剂疗效的一种方法是将其纳入蛋白水解靶向嵌合体（PROTACs）中，这些嵌合体通过多个活性循环降解靶蛋白，表现出更高的抗肿瘤活性。因此，已经开发了基于 KRAS 或 SOS1 定向抑制剂与 von Hippel-Lindau（VHL）或 Cereblon（CRBN）配体偶联的 PROTACs，这些配体引发蛋白酶体降解。这些 PROTACs 中的几种与它们的同源抑制剂相比表现出更高的活性和选择性，但它们在正常组织中的毒性尚不清楚。含有沙利度胺衍生物的 CRBN PROTACs 不能在实验动物中进行测试。对这些 PROTACs 的耐药性是通过下调或失活 CRBN 或功能性 VHL E3 泛素连接酶的因子引起的。尽管已经制备了高度活跃的 KRAS 和 SOS1 PROTACs，但它们的临床应用仍然很困难。
