COUP-TFⅡ拮抗剂设计、合成及其前列腺癌抑制活性研究

It has been reported that the nuclear receptor COUP-TFII is a potential target for the treatment of prostate cancer. Therefore this project will focus on the COUP-TFII antagonist for the drug discovery of the prostate cancer. In the preliminary work, the active small molecular fragments CIA and CIB were found by high-throughput screening of the compounds libraries. The seeding compound (VCT-150805) was found by diversity-oriented synthesis, also the anti-prostate cancer of VCT-150805 was verified in vivo. Therefore, the structure optimization of VCT-150805 will be carried out around the previous work. The structure-activity relationship(SARs) will be summarized by combining the test results in vitro. The leading compounds, potential compounds even the candidate compounds will been determined By repeated structural optimization, evaluation of pharmacodynamics, drug metabolism and safety.

科学研究发现核受体COUP-TFII是前列腺癌治疗的潜在靶点，因此本课题将开展针对抗前列腺癌的COUP-TFII小分子抑制剂的研究。课题前期工作通过高通量筛选发现初具活性的小分子片段或者骨架CIA及CIB，对CIA及CIB两类结构进行多样性的合成后获得苗头化合物VCT-150805，并在裸小鼠体内验证了VCT-150805的抗前列腺癌活性。因此本课题围绕前期工作将开展VCT-150805的结构优化，体外活性测试，构效关系总结等工作，以获得先导化合物，再经过反复的结构优化以及体内外药效，药物代谢以及安全性评价逐步发现更多先导化合物、潜力化合物甚至候选化合物。

科学研究发现核受体COUP-TFII是前列腺癌治疗的潜在靶点，因此本课题将开展针对抗前列腺癌的COUP-TFII小分子抑制剂的研究。根据项目前期工作发现的苗头化合物VCT-150805结构进行结构的改造和优化。通过一系列化合物的合成及体外活性测试发现潜力化合物VCT-8，并在多种肿瘤（LNCaP，PC3，22Rv1）的裸小鼠体内验证了VCT-8的抗前列腺癌活性。这些工作都证实靶点的抗肿瘤作用，为后续新药研究工作提供基础。