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通过基于结构的虚拟查发现和识别一种新的PORCN抑制剂

Xinyu Yang^1,2, Yanbei Li^2,3,4,5, Jingyi Zhou^2,6,7

¹School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.

ACS chemical biology

|May 26, 2025

概括

一种新的 Porcupine (PORCN) 抑制剂,Y-99,已被确定为向癌症中的 Wnt 信号. Y-99表现出强烈的活性,抑制癌细胞增殖和Wnt通路激活.

科学领域:

生物化学生物化学
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

异常的Wnt通路激活驱动瘤发生和癌症进展.
猪 (PORCN) 棕化对Wnt分泌和通路激活至关重要.
波尔CN是Wnt驱动癌症的一个有前途的治疗标.

研究的目的:

确定用于癌症治疗的新型PORCN抑制剂.
描述PORCN抑制剂的结合方式.
为了评估新发现的抑制剂Y-99的疗效,Y-99.

主要方法:

基于结构的虚拟选使用分子对接和模拟.
在体外生化测试以确定抑制活性 (IC50) 和结合亲和力 (KD).
基于细胞的测试来评估抗增殖效应和Wnt通路调节.

主要成果:

发现了一种新型的PORCN抑制剂Y-99.
Y-99证明了Wnt/β-catenin信号传递的强烈抑制 (IC50 = 155.4 nM) 和对PORCN的高结合亲和力 (KD = 33.1 nM).
Y-99显著降低了Wnt成癌细胞的增殖,降低了LRP6酸化和Wnt基因表达 (AXIN2,CCND1).

结论:

Y-99是一种有前途的PORCN抑制剂,通过in silico选确定并在体外验证.
通过抑制Wnt通路激活,Y-99表现出显著的抗癌作用.
Y-99可以为潜在的癌症治疗药物进行进一步的研究和开发.

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