针对KRAS多样性:在癌症治疗中对G12X及以上的共价调制
Tonia Kirschner1,2, Matthias P Müller1,2, Daniel Rauh1,2
1Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227 Dortmund, Germany.
Journal of medicinal chemistry
|April 15, 2024
概括
向KRAS突变,这是20%癌症的关键驱动因素,已经取得了重大进展. 交换机II口袋 (SWIIP) 启用了对KRAS G12C的共价抑制剂,为治疗其他KRAS突变铺平了道路.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- GTPase KRAS蛋白通过在GDP-bound (不活跃) 和GTP-bound (活跃) 状态之间循环,调节细胞信号传递.
- 瘤性KRAS突变在约20%的人类癌症中普遍存在,构成性地激活增殖信号通路.
- 由于其在癌症发展中的作用,KRAS是精密瘤学的关键目标.
研究的目的:
- 审查针对KRAS突变的最新进展,特别关注交换机II口袋 (SWIIP).
- 讨论对KRAS G12C的共价抑制剂的开发及其临床影响.
- 基于KRAS G12C策略,探索针对其他常见的KRAS突变 (G12D,G12V,G12A,G12S,G12R) 的潜力.
主要方法:
- 在KRAS G12C.中的全开关II口袋 (SWIIP) 的共价准.
- 开发和临床批准KRAS G12C抑制剂,如索托拉西布和阿达格拉西布.
- 基于结构的药物设计由KRAS G12C抑制机制提供信息.
主要成果:
- 通过SWIIP成功准KRAS G12C的共价向,导致KRAS G12C突变肺癌获得批准的治疗方法.
- 来自KRAS G12C向的洞察力正在指导其他KRAS突变体的抑制剂的开发.
- 该SWIIP是开发新型KRAS向癌症治疗的验证目标.
结论:
- 针对SWIIP的共价抑制剂的开发代表了针对KRAS的癌症治疗的重大突破.
- 用于KRAS G12C的策略正在适应其他流行KRAS突变,扩大治疗选择.
- 向KRAS突变对各种癌症类型的创新治疗具有重大前景.
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