Kargbo Robert B
Usona Institute, Fitchburg, Wisconsin 53711-5300, United States.
ACS Med Chem Lett. 2023 Oct 19;14(11):1493-1495. doi: 10.1021/acsmedchemlett.3c00442. eCollection 2023 Nov 9.
KRAS, a critical gene involved in cellular processes, can initiate tumor formation when mutated. These mutations occur in about 20-30% of all human cancers, linking KRAS particularly to lung, colorectal, and pancreatic cancers. Its "undruggable" reputation, owing to the difficulty in inhibiting its activity, is being challenged by promising developments. Notably, covalent inhibitors such as sotorasib show success in binding to specific KRAS mutations. Also, PROTACs, an emerging technology, effectively reduce protein levels in the cell, inspiring similar strategies using KRAS-degrading compounds. Novel combination therapies have demonstrated improved anti-tumor effects. This Patent Highlight reveals exemplary KRAS-degrading compounds with anti-tumor activity, effective against both wild-type and mutated KRAS. They present desirable pharmacological properties, promising a revolution in cancer treatment upon further clinical investigation.
KRAS是一种参与细胞过程的关键基因，发生突变时可引发肿瘤形成。这些突变约发生在所有人类癌症的20%-30%中，尤其与肺癌、结直肠癌和胰腺癌相关。由于难以抑制其活性，它有“不可成药”的名声，但一些有前景的进展正在对这一名声提出挑战。值得注意的是，共价抑制剂（如索托拉西布）在与特定KRAS突变结合方面取得了成功。此外，PROTACs（一种新兴技术）能有效降低细胞中的蛋白质水平，这激发了使用KRAS降解化合物的类似策略。新型联合疗法已显示出增强的抗肿瘤效果。本专利亮点揭示了具有抗肿瘤活性的示例性KRAS降解化合物，对野生型和突变型KRAS均有效。它们具有理想的药理学特性，有望在进一步的临床研究后给癌症治疗带来变革。
