■KRAS是一种与肿瘤进展密切相关的关键致癌蛋白,以及瞄准KRAS的困难导致它被归类为不可用的目标。在各种KRAS突变中,KRASG12D非常普遍,代表了一个有前途的治疗靶点。然而,目前还没有批准的抑制剂。
■这篇综述通过搜索PubMed中的相关信息,总结了许多以KRASG12D抑制剂或降解剂为特征的专利和文献,2021年至2024年2月的SciFinder和WebofScience数据库,概述了在设计策略方面抑制KRASG12D的研究进展,化学结构,生物活动,和临床进展。
■自AMG510(Sotorasib)获得批准以来,人们越来越关注KRASG12D的抑制作用,导致相关抑制剂和降解剂的大量报道。其中,MRTX1133,作为第一个进入临床试验的KRASG12D抑制剂,已在各种携带KRASG12D的人类肿瘤异种移植模型中表现出优异的肿瘤抑制。重要的是要注意,然而,了解KRAS抑制引起的获得性耐药机制并开发其他联合疗法至关重要。此外,寻求KRASG12D的共价抑制也具有显著的潜力。
UNASSIGNED: KRAS is a critical oncogenic protein intricately involved in tumor progression, and the difficulty in targeting KRAS has led it to be classified as an \'undruggable target.\' Among the various KRAS mutations, KRASG12D is highly prevalent and represents a promising therapeutic target, yet there are currently no approved inhibitors for it.
UNASSIGNED: This review summarizes numerous patents and literature featuring inhibitors or degraders of KRASG12D through searching relevant information in PubMed, SciFinder and Web of Science databases from 2021 to February 2024, providing an overview of the research progress on inhibiting KRASG12D in terms of design strategies, chemical structures, biological activities, and clinical advancements.
UNASSIGNED: Since the approval of AMG510 (Sotorasib), there has been an increasing focus on the inhibition of KRASG12D, leading to numerous reports of related inhibitors and degraders. Among them, MRTX1133, as the first KRASG12D inhibitor to enter clinical trials, has demonstrated excellent tumor suppression in various KRASG12D-bearing human tumor xenograft models. It is important to note, however, that understanding the mechanisms of acquired resistance caused by KRAS inhibition and developing additional combination therapies is crucial. Moreover, seeking covalent inhibition of KRASG12D also holds significant potential.