MPS1共价抑制剂的设计、合成及其抗乳腺癌作用研究

Mono-polar spindle 1 (MPS1) is a potential therapeutic target for breast cancer, especially triple-negative breast cancer. Currently, all reported MPS1 inhibitors interact with target proteins through non-covalent bonds, and their short response time and rapid occurrence of drug-resistant mutations greatly limit their clinical application. Covalent inhibitors interact directly with target proteins through chemical bonds and have more durable pharmacological effects and higher resistance barriers than reversible inhibitors. This study intends to hunt for first selective MPS1 covalent inhibitors and investigate their in vitro and in vivo anti-breast cancer activities as well as the mechanism of actions. In the early stage, three kinds of derivatives were designed and synthesized by computer-aided drug design methods, and the hit compound with novel scaffold was found, which was preliminarily verified as MPS1 covalent inhibitor and showed good proliferation inhibition activities in a variety of breast cancer cells. Based on the previous basis, we will investigate the drug-target interaction information provided by computer-aided drug design and structural biology to guide further structural optimization and verify the covalent action mode of optimized lead compounds by mass spectrometry and structural biology. Subsequently the optimized lead compounds will be inspected in vitro and in vivo for their anti-breast cancer activity as well as the mechanism of actions to provide the experimental basis for the application of their application in breast cancer treatment.

单级纺锤体蛋白激酶1（MPS1）是一种极具潜力的乳腺癌特别是三阴性乳腺癌的治疗靶点。目前已报道的MPS1抑制剂均通过非共价键与靶点作用，然而短暂的响应时间及快速出现的耐药突变大大限制了其临床应用前景。共价抑制剂直接通过共价键与靶蛋白作用，相比可逆抑制剂具有更持久的药理作用及更高的耐药屏障。本课题拟寻找选择性MPS1共价抑制剂并考察其体内外抗乳腺癌活性及作用机制。前期通过计算机辅助药物设计方法设计、合成了三类衍生物并从中发现了结构新颖的苗头化合物，初步作用机制研究及药效学研究验证了其共价作用模式，且对多种乳腺癌细胞系展现了良好的增殖抑制能力。基于前期基础，本课题将借助计算机辅助药物设计及结构生物学研究指导化合物进一步的结构优化并优选出先导化合物；通过质谱法及结构生物学等方法验证其共价作用模式；并深入考察其体内外抗乳腺癌活性及其作用机制，为其在乳腺癌治疗方面的应用提供实验依据。

单级纺锤体蛋白激酶1（MPS1）是一种极具潜力的乳腺癌特别是三阴性乳腺癌的治疗靶点。目前已报道的MPS1抑制剂均通过非共价键与靶点作用，然而短暂的响应时间及快速出现的耐药突变大大限制了其临床应用前景。共价抑制剂直接通过共价键与靶蛋白作用，相比可逆抑制剂具有更持久的药理作用及更高的耐药屏障。我们在项目前期获得的苗头化合物的基础上，通过系统的构效关系研究对化合物进行优化，根据计算机辅助药物设计和结构生物信息提供的药物-靶点相互作用信息，获得选择性可逆的MPS1抑制剂LZH-2a。然后我们在靠近MPS1铰链区C604位的LZH-2a结构片段中引入了共价反应基团，合成并筛选了100多个合成化合物，发现了一种具有良好的MPS1共价抑制剂MPS1-a7，通过酶动力学方法及质谱孵育法验证其共价作用模式。我们进一步研究了MPS1-7a的抗肿瘤机制，初步确定了该类型化合物在乳腺癌肿瘤模型中的治疗效果，为其在乳腺癌治疗中的应用提供了实验依据。此外，我们发现MPS1抑制通过cGAS-STING先天免疫通路激活乳腺癌抗肿瘤免疫，本研究揭示了MPS1抑制剂在乳腺癌体内外激活抗肿瘤免疫的作用机制，为MPS1抑制剂联合免疫治疗提供理论基础。