DOT1L突变促进肺癌恶性表型的作用机制及小分子靶向药物研究

组蛋白甲基转移酶DOT1L被发现与肺癌等多种肿瘤的发生发展密切相关。近期研究发现DOT1L突变在肺癌中明显增高，然而其潜在致病机制还不清楚。前期，我们在DOT1L酶活性结构域发现功能获得型突变，可促进肺癌恶性表型。机制上初步证明突变诱导的YAP通路激活参与其中，而给予新发现的靶向DOT1L突变的小分子抑制剂则可以阻止突变所致的肺癌增殖，这提示DOT1L突变与肺癌恶性表型密切相关，可能是导致肺癌发生的新机制。然而，对于DOT1L功能获得型突变在肺癌发生发展过程中的确切角色，以及靶向突变的潜在价值还待阐明。为此，本课题拟结合生物学和药物化学等多学科，采用定点突变、定向合成等技术：1）探索DOT1L功能获得型突变促进肺癌恶性表型的分子机制，旨在从表观遗传学角度认知突变在肺癌演进过程中的作用；2）探究以小分子化合物靶向抑制DOT1L突变对肺癌恶性表型的逆转作用，从而为肺癌患者的精准治疗提供新路径。

Histone methyltransferase DOT1L has been found to be closely related to various malignant tumors including lung cancer. Recent studies have found that its mutation is significantly higher in lung cancer, but its internal mechanism is still unclear. Previously, our group identified the gain-of-function mutation in DOT1L enzyme activity domain, which can promote malignant phenotype of lung cancer. The mechanism preliminarily proved that the mutation-induced activation of the YAP signaling pathway is involved, while the newly discovered and synthesized the small molecule inhibitor targeting DOT1L mutation can block the growth of lung cancer caused by the mutation, which suggests that DOT1L mutation is closely related to lung cancer malignancies and may be a novel mechanism leading to lung cancer. However, the exact role of DOT1L gain-of-function mutation in the development and progression of lung cancer, and the potential value of targeted DOT1L mutation remains to be elucidated. To this end, this subject intends to use site-directed mutation, directed synthesis and other technologies in combination with biology and medicinal chemistry and other disciplines: 1) To explore the molecular mechanism by which DOT1L gain-of-function mutation promotes lung cancer malignancies, in order to understand the role of mutation in the evolution of lung cancer from an epigenetic perspective; 2) To explore the reversal effect of inhibiting DOT1L mutation with small molecule compounds on malignant phenotype of lung cancer, so as to provide a new path for precise treatment of lung cancer patients.