PRMT1抑制剂的设计、合成及其抗乳腺癌活性的研究

Protein arginine methyltransferase 1 (PRMT1), a predominant Type I PRMT in mammalian cells, can catalyze protein arginine methylation. PRMT1 has been shown to be over-expressed in breast cancer and hypermethylate the estrogen receptor, leading to enhanced the growth, survival, migration and invasion of breast cancer cells. Therefore, PRMT1 is a potential anti-breast cancer target. However, currently hindering the in vivo activity research of PRMT1 inhibitors is their low in vitro activity. Moreover, our research group found that Asp84 exists near the PRMT1 active site using molecular simulation, and it is expected to increase its inhibited activity. So firstly we will design and synthesize some novel PRMT1 inhibitors based on Asp84 site to enhance its biological activity, which will meet the requirements of in vivo biological experiments. Our research group found that Glu55 on the PRMT1 active site has different electrical property compared with other family members through the sequence and structure alignment. Based on the previous work, we will then optimize the inhibitors’ structures base on Glu55 which might be increase the selectivity, using computer-aided drug design. Newly designed compounds will be synthesized, and tested in vitro and in vivo to evaluate their effects on breast cancer cell behaviour. Hopefully 1-3 inhibitors with high activity and selectivity againist PRMT1 will be identified as leading compound for future research and the development of new drugs for the treatment of breast cancer.

蛋白质精氨酸甲基转移酶1（PRMT1）可以催化蛋白质精氨酸的甲基化。研究发现PRMT1在乳腺癌细胞中高表达，增强了肿瘤细胞的生长、存活、转移和侵袭，因此PRMT1有望成为乳腺癌治疗的新靶点。然而目前阻碍PRMT1抑制剂体内活性研究的关键是其较低的生物活性，本课题组利用分子模拟发现PRMT1活性位点附近存在Asp84空腔，占据该空腔有望提高其抑制活性。因此本项目的首要任务是聚焦于该位点，设计并合成新型PRMT1抑制剂，以期提高其生物活性从而满足体内生物实验的要求。本课题组通过序列和结构比对，发现PRMT1上Glu55位点与其他家族成员电性不同。在完成首要任务的基础上，以Glu55位点作为提高其选择性的位点，结合计算机辅助药物设计对抑制剂进行结构优化，设计并合成有较高活性和选择性的PRMT1抑制剂，并用于体内外抗乳腺癌活性研究，预期最终得到1-3个候选化合物，从而为乳腺癌新药的研发奠定基础。

蛋白质精氨酸甲基转移酶1（PRMT1）可以催化蛋白质精氨酸的甲基化。研究发现PRMT1在 乳腺癌细胞中高表达，增强了肿瘤细胞的生长、存活、转移和侵袭。另外PRMT1在脂肪代谢，糖代谢等疾病中也有重要作用。因此PRMT1有望成为疾病治疗的新靶点。然而目前阻碍PRMT1抑制剂体内活性研究的关键是其较低的生物活性。课题组通过综合应用计算机辅助药物设计、分子对接、分子模拟、有机合成、生物活性测试等技术，设计并合成出一系列新型母核的PRMT1抑制剂，如四氮唑，呋喃，噻唑，共计102个新化合物。初步获得4个对PRMT1有抑制作用的小分子，并进行机理研究，成为抑制肿瘤细胞转移和侵袭的先导化合物。