Development of PROTACS degrading KRAS and SOS1.

IF 2 4区 医学 Q3 ONCOLOGY Oncology Research Pub Date : 2024-07-17 eCollection Date: 2024-01-01 DOI:10.32604/or.2024.051653
Gerhard Hamilton, Marie-Therese Eggerstorfer, Sandra Stickler
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Abstract

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 in vitro and in vivo 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.

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开发降解 KRAS 和 SOS1 的 PROTACS。
克氏大鼠肉瘤病毒-无七之子 1(KRAS-SOS1)轴在胰腺癌、结肠癌和肺癌中优先驱动肿瘤生长。现在,KRAS G12C 突变肿瘤可以通过共价阻断 KRAS 开关 II 结合袋半胱氨酸的抑制剂得到成功治疗。然而,其他 KRAS 突变并不适合治疗,G12C 定向药物 Sotorasib 和 Adragrasib 的反应率仅为 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抑制剂加入蛋白水解靶向嵌合体(PROTACs)中,PROTACs 可降解相关蛋白,并通过多个活性周期表现出更高的抗肿瘤活性。因此,基于 KRAS 或 SOS1 导向抑制剂与 von Hippel-Lindau (VHL) 或 Cereblon (CRBN) 配体的 PROTACs 已被开发出来,这些配体可诱导蛋白酶体降解。与同源抑制剂相比,这些 PROTACs 在体外和体内都显示出更强的活性,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 无法在实验动物中进行测试。对此类 PROTACS 的抗药性是通过 CRBN 或功能性 VHL E3 泛素连接酶因子的下调或失活产生的。虽然高活性的 KRAS 和 SOS1 PROTACs 已被开发出来,但其临床应用仍然困难重重。
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来源期刊
Oncology Research
Oncology Research 医学-肿瘤学
CiteScore
4.40
自引率
0.00%
发文量
56
审稿时长
3 months
期刊介绍: Oncology Research Featuring Preclinical and Clincal Cancer Therapeutics publishes research of the highest quality that contributes to an understanding of cancer in areas of molecular biology, cell biology, biochemistry, biophysics, genetics, biology, endocrinology, and immunology, as well as studies on the mechanism of action of carcinogens and therapeutic agents, reports dealing with cancer prevention and epidemiology, and clinical trials delineating effective new therapeutic regimens.
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