CDKL3在肾细胞癌中功能与分子机制的研究及小分子抑制剂的合成与表征

蛋白激酶的失调导致了以恶性肿瘤为代表的多种重大人类疾病。至今仍有许多我们知之甚少的激酶，其功能和机制亟待发现和探索，例如CDKL3（Cyclin dependent kinase like 3）。申请人通过临床数据库分析及前期实验发现透明细胞肾细胞癌（ccRCC）与CDKL3的显著相关性，并且在细胞水平上初步阐述了CDKL3可作为致癌基因促进肿瘤生长的功能，以及其正向调控Akt/mTOR信号通路与细胞周期的分子机制。基于以上的研究，本项目拟通过肾细胞癌模型系统地研究CDKL激酶家族成员CDKL3。拟在细胞水平上通过细胞生物学和生物化学等手段对该激酶的主要功能和分子机制进行全面且深入的探索，进而利用动物模型并结合临床资源充分支持与验证CDKL3在肾细胞癌中发生发展的病理意义及临床相关性，最后设计并表征CDKL3的特异性小分子抑制剂，未来应用于恶性肿瘤的临床靶向治疗。

The misregulation of human kinases causes multiple severe human diseases, especially malignant tumors. To date, there are still many important kinases whose functions and mechanism are little known to us, including CDKL3 (Cyclin dependent kinase like 3). Based on the analysis of the clinical database and the results of our preliminary experiments, we found that CDKL3 is clinically correlated with clear cell renal cell carcinoma (ccRCC) in a specific and significant manner. We then demonstrated that CDKL3 may function as an oncogene to promote tumor progression under cellular level and further discovered that CDKL3 positively regulate Akt/mTOR signaling pathway and cell cycles in tumors mechanistically. Based on the facts above, we aim to systematically study CDKL3 by employing renal cell carcinoma model in this project. We propose to comprehensively explore the major functions of CDKL3 and deeply dissect its related molecular mechanism. Then, we aim to use animal models and clinical resources to further demonstrate and support the oncogenic function and clinical relevance of CDKL3. At last, we plan to design and characterize the specific small molecule inhibitors targeting CDKL3, which can be potentially applied as the future tumor targeted therapy.