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作为针对黑色素瘤的多酶抑制剂的齐米达-氧醇混合物

Rasha M Allam¹, Ahmed M El Kerdawy², Ahmed E Gouda³

¹Department of Pharmacology, Medical and Clinical Research Institute, National Research Centre, El-Buhouth St., Dokki, P.O. Box 12622, Cairo, Egypt.

Bioorganic chemistry

|March 8, 2024

概括

新的西米达-氧醇结合物显示出对BRAF和其他与癌症相关的标的强有力的多酶抑制. 化合物8e在体外和体内表现出显著的抗瘤活性,提供了一个有前途的新疗法策略.

科学领域:

药用化学医学化学
分子生物学分子生物学
在瘤学瘤学.

背景情况:

激酶抑制剂在癌症治疗中至关重要.
第二种类型的抑制剂提供了一种独特的向激酶的机制.
开发具有提高疗效的新型多酶抑制剂是一个持续的需求.

研究的目的:

设计和合成新型的西米达-氧醇结合物作为II型多酶抑制剂.
评估这些化合物对各种激酶的抑制活性,包括BRAF野生型 (BRAF_WT) 和BRAF V600E.
评估最有前途的化合物的抗癌潜力和作用机制.

主要方法:

合成本齐米达-氧醇合物 (8a-t).
在体外激酶抑制测定对BRAF_WT,BRAF_V600E,VEGFR-2和FGFR-1进行检测.
使用NCI协议和GI₅₀确定细胞毒性查.
在小鼠模型 (B16F10黑色素瘤) 的体内抗瘤疗效研究.
对血管新生标志物,基因表达 (VEGFR-2,FGFR-1),生长因子和蛋白质表达 (Notch1,TGF-β1) 的分析.
分子对接模拟. 分子对接模拟.

主要成果:

化合物8a-t对BRAF_WT表现出中度至强度的抑制 (高达99.61%).
化合物8e,8k,8n和8s显示出对BRAF_WT,BRAF_V600E,VEGFR-2和FGFR-1的强烈抑制.
化合物8e对黑色素瘤细胞系表现出显著的细胞毒性 (GI₅₀ 1.23 - 3.38 μM) 和强大的细胞抑制目标激酶.
在体内,化合物8e显著抑制瘤生长,增加存活率,减少血管生成,并调节关键信号通路 (Notch1,TGF-β1).
分子对接支持化合物8e作为II型激酶抑制剂的作用.

结论:

西米达-氧醇结合物代表了II型多酶抑制剂的一个有前途的类别.
化合物8e具有显著的临床前抗瘤活性和有利的作用机制.
进一步开发化合物8e需要对癌症治疗进行研究.

关键词:

西米达-氧醇混合物在体外和体内实体检查的调查.黑色素瘤是一种黑色素瘤.多种激酶抑制剂多种激酶抑制剂

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