KRAS GTPase泛特异性肿瘤突变型抑制剂的研究。

IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ilya A Eliseev, Dmitrii O Shkil, Valentina S Shumakova, Vladimir V Chernyshov, Konstantin V Balakin, Roman A Ivanov
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引用次数: 0

摘要

KRAS蛋白是癌症治疗的关键靶点之一。共价KRAS抑制剂(sotorasib, adagasib)的临床应用仅限于治疗某些krasg12c介导的癌症类型。此外,使用共价抑制剂有几个缺点,主要局限于特定突变(例如G12C)和肿瘤中潜在的致突变耐药性。最近,一类被称为泛KRAS的新变构抑制剂的第一批代表被发现和研究,因为它们对多种突变形式的KRAS蛋白具有活性。泛kras抑制剂的开发代表了kras介导的癌症治疗方法的一个有希望的新方向。靶向多种突变形式的KRAS的可能性将显著增加从治疗中受益的患者数量,并降低肿瘤中致突变耐药的可能性。本研究回顾了2022年至2024年间发表的专利,这些专利提出了新的泛特异性KRAS抑制剂。对28项专利的考虑包括对所述分子结构的描述,对最具活性和选择性的化合物的鉴定,以及对每个样品的构效关系(SAR)分析的结果。作为这项工作的结果,pan-KRAS抑制剂的一些最活跃的例子的结构特征被确定。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Analysis of Pan-Specific Inhibitors of Oncogenic Mutant Forms of KRAS GTPase.

The KRAS protein is one of the key targets in cancer therapy. The clinical application of covalent KRAS inhibitors (sotorasib, adagrasib) is limited to the treatment of only certain KRASG12C-mediated types of cancer. In addition, using covalent inhibitors has several drawbacks, the main ones being limited to specific mutations (e.g., G12C) and the potential development of mutagenic resistance in tumors. Recently, the first representatives of a new class of allosteric inhibitors, termed pan-KRAS, have been discovered and studied due to their activity against multiple mutant forms of the KRAS protein. The development of pan-KRAS inhibitors represents a promising new direction in the therapeutic approach to treating KRAS-mediated cancers. The possibility to target multiple mutant forms of KRAS will significantly enlarge the number of patients that benefit from the therapy and reduce the likelihood of mutagenic resistance in tumors. This study reviews patents published between 2022 and 2024 that present new pan-specific KRAS inhibitors. The consideration of 28 patents included descriptions of the structures of the presented molecules, identification of the most active and selective examples of compounds, as well as results from structure-activity relationship (SAR) analyses for each sample. As a result of this work, some structural features of the most active examples of pan-KRAS inhibitors were identified.

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来源期刊
Current medicinal chemistry
Current medicinal chemistry 医学-生化与分子生物学
CiteScore
8.60
自引率
2.40%
发文量
468
审稿时长
3 months
期刊介绍: Aims & Scope Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. The journal also publishes reviews on recent patents. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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