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通过基于片段的药物设计方法开发选择性I类蛋白质氨酸甲基转移酶抑制剂

Debomita Bhattacharya¹, Alice Shi Ming Li², Barnali Paul¹

¹Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology (IICB), 4 Raja S.C. Mullick Road, Kolkata 700032, India.

European journal of medicinal chemistry

|August 19, 2023

概括

研究人员使用基于片段的方法开发了强效和选择性的I类蛋白质氨酸甲基转移酶 (PRMT) 抑制剂. 这些新型化合物显示出治疗与异常PRMT表达相关的疾病的前景.

科学领域:

生物化学生物化学
药用化学医学化学
药物发现药物发现药物发现

背景情况:

蛋白质氨酸甲基转移酶 (PRMTs) 是参与蛋白质甲基化中的关键酶.
异常的PRMT表达与各种疾病有关,突出了它们的治疗潜力.
现有的PRMT抑制剂正在临床开发中,验证了它们作为药物标的重要性.

研究的目的:

使用基于片段的药物发现方法发现选择性I类PRMT抑制剂.
通过基于结构的连接体设计来优化碎片命中.
为治疗应用开发强效和选择性小分子抑制剂.

主要方法:

采用基于片段的方法来识别初始的PRMT抑制剂.
利用基于结构的配体优化,将碎片击中到quinazoline核心.
进行碎片生长以增强结合亲和力和选择性.

主要成果:

已识别出强效的I类PRMT抑制剂,化合物55和56,对PRMT4.4的IC50值为92nM和37nM.
为开发的抑制剂建立了明确的结构-活性关系 (SAR).
与31个甲基转移酶的小组相比,获得了大约100倍的选择性.

结论:

通过系统的基于片段的方法,成功开发出强效和选择性的I类PRMT抑制剂.
化合物显示出作为治疗剂进一步开发的巨大潜力.
这些新型抑制剂为在疾病治疗中向PRMT4提供了新的选择.

关键词:

基于碎片的药物设计.在PKMTs中,PKMTs是PKMTs.对于PRMTs来说,这是一个很大的问题.选择性抑制剂选择性抑制剂

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