新型肿瘤抑制剂Compound 2靶向降解癌性蛋白EZH2作用及机制研究

The enhancer of zeste homolog 2 (EZH2) has been reported to maintain malignant phenotype and transformation of tumor. As the protein is abnormally high-expressed and closely related to malignancy of precancerous lesions, EZH2 are considered to be the key target of antitumor drug. But the existing development strategy of the single inhibition on the catalytic activity of EZH2 cannot exclude other positive effects of EZH2 on tumor growth besides the catalytic activity, which limits the antitumor efficacy of this class of drugs. Our previous study reveals gambogenic acid derivatives Compound 2 represents a novel EZH2 inhibitor, protected by the Chinese invention patent. Compound 2 is not a simulation of existing enzyme activity inhibitor, but can be more thoroughly remove EZH2 protein to shut down its tumor promoting function. The molecular mechanisms for the further study of Compound 2-induced EZH2 degradation will reveal its targeting effectiveness and specificity. This study intends to combine synthetic chemistry, computational chemistry, molecular biology, cell biology and tumor biology research methods, in order to find structure-activity relationship, the role of Compound 2 on appropriate tumor types, clear the effect of Compound 2 targeting and specificity. The important significance of this study is to propose a novel EZH2 inhibitors screening model, pioneering a new targeting strategy of EZH2, promoting the drugs for clinical application and transformation in the international market.

异常高表达的EZH2与肿瘤癌前病变的恶性转化和恶性表型的维持密切相关。该蛋白既可作为组蛋白甲基转移酶沉默抑癌基因表达，又可作为共转录因子发挥非酶活性促进癌基因表达，是公认的重要抗肿瘤药物靶标。但现有的EZH2抑制剂仅能降低EZH2的酶活性，不能去除EZH2酶活以外的、其他促肿瘤生长功能，这限制了此类药物的抗肿瘤效果和应用范围。我们的前期研究证实，藤黄精酸衍生物Compound 2代表一类新型EZH2抑制剂直接诱导EZH2降解，使得EZH2作为催化酶和共转录因子的物质基础彻底丧失，可更有效地关闭EZH2功能。为进一步阐述该化合物对EZH2蛋白稳定性的影响和机制，本研究拟综合多学科手段分析化合物-蛋白质结合的化学键类型和构效关系，寻找最敏感肿瘤类型，提高其抗肿瘤效果。本研究的重要意义在于开拓一种靶向降解EZH2、彻底关闭其功能的新型抑制策略，推动新型靶向抗肿瘤药物的成果转化和临床应用。

异常高表达的EZH2与肿瘤癌前病变的恶性转化和恶性表型的维持密切相关。该蛋白既可作.为组蛋白甲基转移酶沉默抑癌基因表达，又可作为共转录因子发挥非酶活性促进癌基因表达，.是公认的重要抗肿瘤药物靶标。但现有的EZH2抑制剂仅能降低EZH2的酶活性，不能去除EZH2酶活以外的、其他促肿瘤生长功能，这限制了此类药物的抗肿瘤效果和应用范围。我们的研究证实，藤黄精酸衍生物Compound 2代表一类新型EZH2抑制剂直接诱导EZH2降解，使得EZH2作为催化酶和共转录因子的物质基础彻底丧失，可更有效地关闭EZH2功能。本研究综合多学科手段分析化合物-蛋白质结合的化学键类型和构效关系，寻找最敏感肿瘤类型，提高其抗肿瘤效果，阐述该化合物对EZH2蛋白稳定性的影响和机制。本研究的重要意义在于开拓一种靶向降解EZH2、彻底关闭其功能的新型抑制策略，推动新型靶向抗肿瘤药物的成果转化和临床应用。

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