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从虚拟查和理性结构优化中发现基于素的新型KRAS-G12C抑制剂

Jian-Tao Shi¹, Su-Juan Hou¹, Lei Cheng¹

¹School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China.

Bioorganic chemistry

|May 21, 2024

概括

新的库马林衍生物对KRAS-G12C突变癌症表现出强大的抑制作用. 化合物K45表现出显著的抗增殖作用,并诱导细胞灭绝,为KRAS-G12C驱动的恶性瘤提供了一个有前途的新治疗策略.

科学领域:

药用化学医学化学
在瘤学瘤学.
分子生物学分子生物学

背景情况:

针对KRAS-G12C突变癌症的向疗法正在推进,但适应性耐药性需要新的抑制剂.
开发新的结构抑制剂对于克服当前KRAS-G12C治疗的局限性至关重要.

研究的目的:

确定和描述新型氨酸衍生物作为KRAS-G12C的强有力的抑制剂.
在临床前癌症模型中评估化合物K45的疗效和作用机制.

主要方法:

虚拟查和基于合理结构的优化被用来发现新的抑制剂.
在KRAS-G12C突变癌细胞系 (NCI-H23,NCI-H358) 中使用IC50值来评估抗增殖活性.
西方涂抹用于分析下游信号通路 (ERK,AKT) 和与亡相关的蛋白质 (BAD,BAX);进行了分子对接.

主要成果:

化合物K45对NCI-H23 (IC50 = 0.77μM) 和NCI-H358 (IC50 = 1.50μM) 细胞表现出强烈的抗增殖活性,显著优于阳性对照ARS1620.
K45有效地降低了KRAS (KRAS GTP) 的活性形式,导致NCI-H23细胞下游效应因子ERK和AKT的酸化降低.
在NCI-H23细胞中,K45诱导了亡,通过上调亡蛋白BAD和BAX的表达.
对接研究表明,K45的3 - 纳甲基与KRAS-G12C的密码口袋中的关键残留物 (Gln99,Val9) 相互作用,增强结合亲和力.

结论:

K45是一种高度强大的KRAS-G12C抑制剂,具有涉及途径抑制和亡诱导的有希望的作用机制.
K45的新型结构特征表明它有潜力进一步发展为治疗KRAS-G12C驱动癌症的治疗剂.
这些发现凸显了库马林衍生物在向KRAS-G12C突变方面的治疗潜力.

关键词:

它具有抗增殖效果的作用.库马林是一种素.在KRAS-G12C中使用.沙尔 (SARs) 是一种针对性搜索引擎.

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