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探索KRAS(G12D) 与突变选择性单体抑制剂的交换机II口袋形状

Padma Akkapeddi¹, Takamitsu Hattori^1,2, Imran Khan^3,4

¹Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016.

Proceedings of the National Academy of Sciences of the United States of America

|July 3, 2023

概括

新的合成结合蛋白,称为单体,选择性地向KRAS (G12D) 癌症突变. 这些单体抑制KRAS (G12D) 信号和瘤生长,为癌症治疗提供了一个有前途的途径.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
蛋白质工程是指蛋白质工程.

背景情况:

KRAS ((G12D) 突变是癌症的常见驱动因素,特别是胰腺癌.
针对特定的KRAS突变仍然是癌症治疗中的一个挑战.

研究的目的:

开发用于KRAS (G12D) 蛋白的新型,高度选择性的抑制剂.
描述KRAS (G12D) 抑制的结合机制和结构基础.

主要方法:

开发了 KRAS ((G12D) 选择性单体 (合成结合蛋白).
结晶学研究以确定抑制剂-标相互作用.
结构引导的亲和力成熟和深度突变扫描.
在体外和细胞测试以评估信号和瘤发生的抑制.

主要成果:

单体对 KRAS ((G12D) 具有较高的选择性,相对于野生类型的 KRAS 和其他 RAS 异型.
结构分析揭示了S-II口袋内独特的结合相互作用,包括直接识别Asp12.
亲和力成熟产生了具有纳米分子结合亲和力的单体 (K_D).
在细胞模型中,基因编码的单体抑制了KRAS ((G12D) 驱动的信号传递和瘤生长.

结论:

单体代表了一个有前途的类 KRAS ((G12D) 选择性抑制剂.
可以利用S-II口袋的可塑性来设计下一代癌症治疗方法.
这些发现为开发针对KRAS突变癌症的向治疗提供了基础.

关键词:

形状塑性形状塑性形状塑性发现药物的发现.细胞内生物制剂细胞内生物制剂蛋白质工程工程蛋白质工程蛋白质与蛋白质的相互作用

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