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设计,合成和生物评估氧基纳林衍生物作为潜在的EGFR

Yanliang Guo¹, Biao Gao², Peng Gao²

¹Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, PR China; Jiangsu Hansoh Pharmaceutical Group CO., LTD., Lianyungang 222000, PR China.

Bioorganic & medicinal chemistry

|June 3, 2023

概括

研究人员开发了新型第四代表皮生长因子受体 (EGFR) 抑制剂,以对抗具有C797S突变的非小细胞肺癌 (NSCLC). 化合物8a显示出强大的抗瘤功效,显示出作为一种新的NSCLC治疗方法的显著潜力.

科学领域:

药用化学医学化学
在瘤学瘤学.
药理学药理学是指药理学的学科.

背景情况:

非小细胞肺癌 (NSCLC) 构成了重大的健康挑战,特别是当由表皮生长因子受体 (EGFR) 突变驱动时.
耐药性突变的出现,如C797S,限制了现有的EGFR抑制剂的疗效,需要开发下一代疗法.
第四代EGFR抑制剂对于克服耐药机制和改善NSCLC患者治疗结果至关重要.

研究的目的:

设计和合成基于布里加替尼基架的新型第四代EGFR抑制剂.
评估合成化合物对EGFR突变的抑制活性和选择性,包括C797S耐药性突变.
评估有希望的候选药物的体外和体内抗瘤疗效和药理动力学特性.

主要方法:

基于结构的药物设计和氧基纳林衍生物的化学合成.
在体外酶分析以确定对各种EGFR突变的抑制活性 (例如,L858R/T790M/C797S,Del19/T790M/C797S).
基于细胞的测定使用过度表达特定EGFR突变的Ba/F3细胞.
在异种移植小鼠模型中进行的药理动力学研究和体内抗瘤疗效评估.

主要成果:

与布里加替尼相比,合成的化合物显著改善了对EGFR L858R/T790M/C797S和Del19/T790M/C797S突变体的抑制活性和选择性.
化合物8a在该系列中表现出最强烈的体外生物活性.
化合物8a表现出有利的药理动力学特性,并在Ba/F3-EGFRDel19/T790M/C797S异种移植小鼠模型中达到82.60%的瘤生长抑制,剂量为30 mg/kg.

结论:

化合物8a是新型第四代EGFR小分子抑制剂的有希望的候选药物.
8a显示了治疗含有EGFR突变的NSCLC的高潜力,特别是C797S耐药性突变.
进一步开发8a可能会为具有有限治疗选择的NSCLC患者带来新的治疗选择.

关键词:

耐药性耐药性耐药性耐药性这是一种EGFR抑制剂.在EGFR的三重突变中.在NSCLCLC中,我们可以看到.

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