1. 毕业设计（论文）的内容和要求

课题的基本要求：（1）通过查阅文献，了解该课题的国内外研究现状；（2）学习和掌握有关计算软件的使用；（3）选择对于这两种激酶具有选择性的抑制剂小分子为研究体系，利用Amber软件对体系进行模拟计算，分析体系在溶剂中的构象变化；（4）分析计算结果，撰写毕业论文。

预定完成任务及时间：2016年6月7日

2. 参考文献

Lolli, G., Lowe, E. D., Brown, N. R. Johnson, L. N. The crystal structure of human CDK7 and its protein recognition properties. Structure. 12 (2004) 2067-79. [2] Ganuza, M. Santamaria, D. Cdk7: open questions beyond the prevailing model. Cell Cycle. 11 (2012) 3519-3520. [3] Shchebet, A., Karpiuk, O., Kremmer, E., Eick, D. Johnsen, S. A. Phosphorylation by cyclin-dependent kinase-9 controls ubiquitin-conjugating enzyme-2A function. Cell Cycle. 11 (2012) 2122-7. [4] Hole, A. J., Baumli, S., Shao, H., Shi, S., Huang, S., Pepper, C., Fischer, P. M., Wang, S., Endicott, J. A. Noble, M. E. Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity. J Med Chem. 56 (2013) 660-70. [5] Shao, H., Shi, S., Huang, S., Hole, A. J., Abbas, A. Y., Baumli, S., Liu, X., Lam, F., Foley, D. W., Fischer, P. M., Noble, M., Endicott, J. A., Pepper, C. Wang, S. Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors: synthesis, X-ray crystal structures, structure-activity relationship, and anticancer activities. J Med Chem. 56 (2013) 640-59. [6] Albert, T., Rigault, C., Eickhoff, J., Baumgart, K., Antrecht, C., Klebl, B., Mittler, G. Meisterernst, M. Characterization of molecular and cellular functions of the cyclin‐dependent kinase CDK9 using a novel specific inhibitor. British Journal of Pharmacology. 171 (2014) 55-68. [7] C George Priya Doss, N. N., Chiranjib Chakraborty. Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach. Human Genomics. 7 (2013). [8] Huang, C. H., Lujambio, A., Zuber, J., Tschaharganeh, D. F., Doran, M. G., Evans, M. J., Kitzing, T., Zhu, N., de Stanchina, E., Sawyers, C. L., Armstrong, S. A., Lewis, J. S., Sherr, C. J. Lowe, S. W. CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev. 28 (2014) 1800-14. [9] Randjelovic, J., Eric, S. Savic, V. Computational study and peptide inhibitors design for the CDK9 - cyclin T1 complex. J Mol Model. 19 (2013) 1711-25. [10] Hui Zhanga, S.-H. P. SIRT2 directs the replication stress response through CDK9 deacetylation. PNAS. 110 (2013) 13546-13551. [11] Sonja Baumli, G. L., Edward D Lowe1, Sonia Troiani,Luisa Rusconi, Alex N Bullock, Judit E′ Debreczeni, Stefan Knapp and Louise N Johnson. The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. The EMBO Journal. 27 (2008) 1907-1918. [12] Ganuza, M., Saiz-Ladera, C., Canamero, M., Gomez, G., Schneider, R., Blasco, M. A., Pisano, D., Paramio, J. M., Santamaria, D. Barbacid, M. Genetic inactivation of Cdk7 leads to cell cycle arrest and induces premature aging due to adult stem cell exhaustion. EMBO J. 31 (2012) 2498-510. [13] Wu, Y., Chen, C., Sun, X., Shi, X., Jin, B., Ding, K., Yeung, S. C. Pan, J. Cyclin-dependent kinase 7/9 inhibitor SNS-032 abrogates FIP1-like-1[1] Lolli, G., Lowe, E. D., Brown, N. R. Johnson, L. N. The crystal structure of human CDK7 and its protein recognition properties. Structure. 12 (2004) 2067-79. [2] Ganuza, M. Santamaria, D. Cdk7: open questions beyond the prevailing model. Cell Cycle. 11 (2012) 3519-3520. [3] Shchebet, A., Karpiuk, O., Kremmer, E., Eick, D. Johnsen, S. A. Phosphorylation by cyclin-dependent kinase-9 controls ubiquitin-conjugating enzyme-2A function. Cell Cycle. 11 (2012) 2122-7. [4] Hole, A. J., Baumli, S., Shao, H., Shi, S., Huang, S., Pepper, C., Fischer, P. M., Wang, S., Endicott, J. A. Noble, M. E. Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity. J Med Chem. 56 (2013) 660-70. [5] Shao, H., Shi, S., Huang, S., Hole, A. J., Abbas, A. Y., Baumli, S., Liu, X., Lam, F., Foley, D. W., Fischer, P. M., Noble, M., Endicott, J. A., Pepper, C. Wang, S. Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors: synthesis, X-ray crystal structures, structure-activity relationship, and anticancer activities. J Med Chem. 56 (2013) 640-59. [6] Albert, T., Rigault, C., Eickhoff, J., Baumgart, K., Antrecht, C., Klebl, B., Mittler, G. Meisterernst, M. Characterization of molecular and cellular functions of the cyclin‐dependent kinase CDK9 using a novel specific inhibitor. British Journal of Pharmacology. 171 (2014) 55-68. [7] C George Priya Doss, N. N., Chiranjib Chakraborty. Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach. Human Genomics. 7 (2013). [8] Huang, C. H., Lujambio, A., Zuber, J., Tschaharganeh, D. F., Doran, M. G., Evans, M. J., Kitzing, T., Zhu, N., de Stanchina, E., Sawyers, C. L., Armstrong, S. A., Lewis, J. S., Sherr, C. J. Lowe, S. W. CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev. 28 (2014) 1800-14. [9] Randjelovic, J., Eric, S. Savic, V. Computational study and peptide inhibitors design for the CDK9 - cyclin T1 complex. J Mol Model. 19 (2013) 1711-25. [10] Hui Zhanga, S.-H. P. SIRT2 directs the replication stress response through CDK9 deacetylation. PNAS. 110 (2013) 13546-13551. [11] Sonja Baumli, G. L., Edward D Lowe1, Sonia Troiani,Luisa Rusconi, Alex N Bullock, Judit E′ Debreczeni, Stefan Knapp and Louise N Johnson. The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. The EMBO Journal. 27 (2008) 1907-1918. [12] Ganuza, M., Saiz-Ladera, C., Canamero, M., Gomez, G., Schneider, R., Blasco, M. A., Pisano, D., Paramio, J. M., Santamaria, D. Barbacid, M. Genetic inactivation of Cdk7 leads to cell cycle arrest and induces premature aging due to adult stem cell exhaustion. EMBO J. 31 (2012) 2498-510. [13] Wu, Y., Chen, C., Sun, X., Shi, X., Jin, B., Ding, K., Yeung, S. C. Pan, J. Cyclin-dependent kinase 7/9 inhibitor SNS-032 abrogates FIP1-like-1 platelet-derived growth factor receptor alpha and bcr-abl oncogene addiction in malignant hematologic cells. Clin Cancer Res. 18 (2012) 1966-78. [14] Asghar, U., Witkiewicz, A. K., Turner, N. C. Knudsen, E. S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 14 (2015) 130-46. [15] Beigi, F., Schmeckpeper, J., Pow-Anpongkul, P., Payne, J. A., Zhang, L., Zhang, Z., Huang, J., Mirotsou, M. Dzau, V. J. C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway. Circ Res. 113 (2013) 372-80. [16] Nekhai, S., Petukhov, M. Breuer, D. Regulation of CDK9 activity by phosphorylation and dephosphorylation. Biomed Res Int. 2014 (2014) 964964. [17] Krystof, V., Baumli, S. Furst, R. Perspective of Cyclin-dependent kinase 9 (CDK9) as a Drug Target. Current Pharmaceutical Design. 18 (2012) 2883-2890.

3. 毕业设计（论文）进程安排

2016-02-25~2016-03-25 系统地检索和阅读相关中外文文献，了解该课题的国内外研究现状。

对cdk7和cdk9的结构和性质，计算机模拟软件gaussian 09、autodock4.0、amber 10，前人的研究等有所了解，完成开题报告。

2016-03-25~2016-05-10 进一步学习和掌握有关计算软件的使用，用gaussian 09优化4-(噻唑-5-基)-2苯胺基嘧啶抑制剂的几何结构，并利用autodock4.0将其最优结构和cdk7以及cdk9进行对接。