臺灣博碩士論文加值系統

本論文主旨在設計與合成吲唑化合物為北極光激酶抑制劑，期望以此發展為抗癌標靶藥物。以ATP競爭抑制劑概念為基礎進行開發，首先利用子結構(sub-structure)進行分子庫搜尋，篩選出潛力化合物74為修飾目標，利用電腦輔助片段基礎設計引入丙烯醯胺片段得到化合物50a，再以循理性藥物設計方式，於吲唑骨架五號位置引入苯磺醯胺片段發展出先導化合物74，並從電腦輔助模型瞭解其結構與北極光激酶之間的作用力，接著建構先導化合物74之結構活性關係與類藥性質的改善用以提升癌細胞株抑制活性，最後，進行多靶點激酶抑制活性與北極光激酶家族選擇性抑制活性測試探討此吲唑系列對於激酶選擇性抑制的表現。

This dissertation is concerned with the development of indazole-based derivatives as Aurora kinases inhibitors. Based on the concept of ATP competitive inhibitors, indazole skeleton was selected as a starting point. Utilizing our in-house database by sub-structure screening, hit compound 47 was identified as the initial hit which showed weak inhibition against Aurora A. Compound 50a was further synthesized by using in silico FBDD techniques and resulting in 10-fold potency improvement. Following by rational drug design, the carboxylic acid group extended from aniline at the C-3 of indazole core and phenylsulfonamide group at the C-5 of indazole core are newly identified to improve the potency as lead compound 74. SAR of lead compound 74 was constructed as well as the drug-like property was modified to enhance activity against cancer cell proliferation. Finally, kinases profiling and isoform selectivity were assayed and discussed through computer assisted docking model.

中文摘要 i
Abstract ii
謝誌 iii
目錄 iv
表目錄 x
圖目錄 xii
流程目錄 xvi
縮寫對照表 xviii
壹、緒論 1
1.1 前言 1
1.2 癌症治療 2
1.2.1 癌症化療藥物之分類 3
1.2.1.1 烷化劑 (Alkylating agents) 3
1.2.1.2 抗代謝藥物 (Antimetabolic agents) 4
1.2.1.3 干擾DNA複製相關藥物 5
1.2.1.4 微管蛋白抑制劑 (Microtubule inhibitor) 8
1.2.1.5 血管新生抑制劑 (Anti-angiogenesis inhibitor) 9
1.2.1.6 其他 10
1.2.2 癌症標靶治療藥物 11
1.2.2.1 抗血管增生之標靶藥物 11
1.2.2.2 癌細胞表面抗原之標靶藥物 12
1.2.2.3 癌細胞訊息傳遞路徑之標靶藥物 12
1.2.3 癌症治療藥物發展趨勢 14
1.3 蛋白質激酶 14
1.3.1 激酶活化區與ATP作用之區域 15
1.3.2 以激酶為標靶的抗癌藥物 16
1.4 激酶與細胞週期 (Cell cycle) 21
1.5 北極光激酶 (Aurora kinases) 24
1.5.1 北極光激酶和有絲分裂 (Mitosis) 25
1.5.1.1 北極光激酶A (Aurora A) 26
1.5.1.2 北極光激酶B (Aurora B) 27
1.5.1.3 北極光激酶C (Aurora C) 28
1.5.2 北極光激酶與癌症 28
1.5.3 北極光激酶抑制劑之發展 30
1.5.3.1 泛北極光激酶抑制劑 33
1.5.3.2 北極光激酶A選擇性抑制劑 34
1.5.3.3 北極光激酶B選擇性抑制劑 35
1.6 生藥所北極光激酶抑制劑之發展 36
1.6.1 呋喃駢嘧啶骨架為潛力化合物 37
1.6.2 高通量平行合成策略 39
1.6.3 北極光激酶抑制劑10的結構修飾與性質優化 40
1.6.4 電腦輔助藥物設計用於開發北極光激酶抑制劑 40
1.6.4.1 以構效關係開發喹唑啉衍生物為北極光激酶抑制劑 42
1.6.4.2 以高通量篩選北極光激酶抑制劑 43
1.6.4.3 電腦輔助藥物用於雙重抑制劑開發 44
貳、研究動機 46
2.1 新藥的開發 46
2.1.1 潛力化合物的尋找 47
2.1.2 先導化合物的優化策略 48
2.1.3 候選藥物的產出 49
2.2 吲唑(indazole)骨架衍生物為激酶抑制劑 51
2.2.1 吲唑骨架衍生物為JNK激酶抑制劑 52
2.2.2 吲唑骨架衍生物為Mps1激酶抑制劑 54
2.2.3 吲唑骨架衍生物為ITK激酶抑制劑 54
2.2.4 吲唑骨架衍生物為PLK4激酶抑制劑 56
2.2.5 吲唑骨架衍生物為各類激酶抑制劑 57
2.3 研究構想 60
2.4 生物活性測試分析 62
2.4.1 酵素活性分析 62
2.4.2 癌細胞株生長抑制活性測試 64
參、結果與討論 65
3.1 篩選潛力化合物(hit compound) 65
3.2 潛力化合物修飾策略 67
3.2.1 電腦輔助片段基礎藥物設計之方法 67
3.2.1 丙烯醯胺化合物50a的合成與結構修飾 70
3.2.2 丙烯醯胺化合物50a之結構活性關係 71
3.2.3 吲唑衍生物與北極光激酶之電腦輔助模型 74
3.2.4 潛力化合物結構修飾之結論 75
3.3 循理性藥物設計 76
3.3.1 循理性藥物設計的合成策略 78
3.3.2 循理性藥物設計之合成 78
3.3.3 循理性藥物設計之結構活性關係 82
3.3.4 吲唑骨架的5號位置官能基修飾與合成 83
3.3.5 吲唑骨架的5號位置修飾之結構活性關係 86
3.3.6 先導化合物74與北極光激酶之電腦輔助模型 88
3.4 先導化合物74結構修飾策略 89
3.4.1 先導化合物74結構修飾之合成 89
3.4.2 先導化合物74之結構活性關係 91
3.4.3 先導化合物74結構修飾之結論 94
3.5 先導化合物74性質優化策略 95
3.5.1 先導化合物74性質優化之合成 98
3.5.2 先導化合物74性質優化之生物活性分析 99
3.5.3 混成設計化合物之合成與結構活性關係 102
3.5.4 先導化合物74性質優化之結論 106
3.6 激酶選擇性的探討 107
3.6.1 多靶點激酶抑制活性分析 108
3.6.2 北極光激酶家族選擇性探討 110
肆、總結 115
伍、實驗部份 118
5.1 一般實驗方法 118
5.2 化合物之實驗步驟與光譜資料 120
陸、參考資料 199

附錄一 電腦輔助片段篩選藥物之化合物 210
附錄二 化合物之核磁共振光譜圖 220
附錄三 化合物74細胞膜穿透度試驗結果 316
附錄四 化合物之編號對照表 319
附錄五 生物活性測試分析方法 322
附錄六 口試投影片 325
附錄七 BPR2K吲唑系列化合物與生物活性 350
附錄八 發表之論文 358

1. 行政院衛生福利部. 中華民國104年死因統計資料. 2016.
2. Ishida, Y.; Agata, Y.; Shibahara, K. ; Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992, 11, 3887-3895.
3. Leach, D. R.; Krummel, M. F.; Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996, 271, 1734-1736.
4. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12, 252-264.
5. Teicher, B. A. Cancer Therapeutics: Experimental and Clinical Agents. Humana Press: 1996.
6. Kirkwood, J. M.; Lotze, M. T.; Yasko, J. M. Current Cancer Therapeutics. Current Medicine Group: 2013.
7. Avendano, C.; Menendez, J.C. Medicinal Chemistry of Anticancer Drugs. Elsevier Science: 2015.
8. Goodman, L. S.; Wintrobe, M. M.; Dameshek, W.; Good, M. J.; Gilman, A. Z.; McLennan, M. T. NIitrogen Mustard Therapy. Use of methyl-bis(beta-Chloroethyl) amine hydrochloride and tris(beta-chloroethyl)amine hydrochloride for Hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. J. Am. Med. Ass. 1946, 132, 126-132.
9. Manegold, C. Pemetrexed (alimta, MTA, multitargeted antifolate, LY231514) for malignant pleural mesothelioma. Semin. Oncol. 2003, 30, 32-36.
10. Vora, A.; Mitchell, C. D.; Lennard, L.; Eden, T. O. B.; Kinsey, S. E.; Lilleyman, J.; Richards, S. M. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. The Lancet. 2006, 368, 1339-1348.
11. Fox, E. J. Management of worsening multiple sclerosis with mitoxantrone: A review. Clin. Ther. 2006, 28, 461-474.
12. Kopka, M. L.; Yoon, C.; Goodsell, D.; Pjura, P.; Dickerson, R. E. The molecular origin of DNA-drug specificity in netropsin and distamycin. Proc. Nati. Acad. Sci. 1985, 82, 1376-1380.
13. Hiraku, Y.; Oikawa, S.; Kawanishi, S. Distamycin A, a minor groove binder, changes enediyne-induced DNA cleavage sites and enhances apoptosis. Nucleic Acid Res. Suppl. 2002, 95-96.
14. Sugiura, Y.; Kikuchi, T. Formation of superoxide and hydroxyl radicals in iron(II)-bleomycin-oxygen system : electron spin resonance detection by spin trapping. J. Antibiot. 1978, 31, 1310-1312.
15. Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail, A. T.; Sim, G. A. Plant Antitumor Agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminata. J. Am. Chem. Soc. 1966, 88, 3888–3890.
16. Ulukan, H.; Swaan, P. W. Camptothecins: a review of their chemotherapeutic potential. Drugs 2002, 62, 2039-2057.
17. Hande, K. R. Etoposide: Four decades of development of a topoisomerase II inhibitor. Eur. J. Cancer 1998, 34, 1514-1521.
18. Jordan, A.; Hadfield, J. A.; Lawrence, N. J.; McGown, A. T. Tubulin as a target for anticancer drugs: agents which interact with the mitotic spindle. Med. Res. Rev. 1998, 18, 259-296.
19. Manfredi, J. J.; Horwitz, S. B. Taxol: an antimitotic agent with a new mechanism of action. Pharmacol. Ther. 1984, 25, 83-125.
20. Thoret, S.; Gue´ritte, F.; Gue´nard, D.; Dubois, J. Semisynthesis and biological evaluation of a novel D-seco docetaxel analogue. Org. Lett. 2006, 8, 2301-2304.
21. Pettit, G. R.; Singh, S. B.; Niven, M. L.; Hamel, E.; Schmidt, J. M. Isolation, structure, and synthesis of Combretastatins A-1 and B-1, potent new inhibitors of microtubule assembly, derived from Combretum caffrum. J. Nat. Prod. 1987, 50, 119-131.
22. Hsieh, H. P.; Liou, J. P. ; Mahindroo, N. Pharmaceutical design of antimitotic agentsbased on Combretastatins. Curr. Pharm. Des. 2005, 11, 1655-1677.
23. Mahindroo, N.; Liou, J. P.; Chang, J. Y.; Hsieh, H. P. Antitubulin agents for the treatment of cancer – a medicinal chemistry update. Expert Opin. Ther. Patents 2006, 16, 647-691.
24. Folkman, J. Tumor angiogenesis factor. Cancer Res. 1974, 34, 2109-2113.
25. Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med. 1995, 1, 27 - 30.
26. Shih, T.; Lindley, C. Bevacizumab: An angiogenessis inhibitor for the treatment of solid malignancies. Clin. Ther. 2006, 28, 1779-1802.
27. Alderden, R. A.; Hall, M. D.; Hambley, T. W. The discovery and development of Cisplatin. J. Chem. Educ. 2006, 83, 728-734.
28. Jordan, V. C. A current view of tamoxifen for the treatment and prevention of breast cancer. Br. J. Pharmacol. 1993, 110, 507-517.
29. Gerber, D. E. Targeted therapies : A new generation of cancer treatments. Am. Fam. Physician 2008, 77, 311-319.
30. Keating, G. M.; Santoro, A. Sorafenib : A review of its use in ddvanced hepatocellular carcinoma. Drugs 2012, 69, 223-240.
31. Gan, H. K.; Seruga, B.; Knox, J. J. Sunitinib in solid tumors. Expert Opin. Investig. Drugs 2009, 18, 821-834.
32. Scott, S. D. Rituximab: a new therapeutic monoclonal antibody for non-Hodgkin's lymphoma. Cancer Pract. 1998, 6, 195-197.
33. Bross, P. F.; Beitz, J.; Chen, G.; Chen, X. H.; Duffy, E.; Kieffer, L.; Roy, S.; Sridhara, R.; Rahman, A.; Williams, G.; Pazdur, R. Approval summary: Gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001, 7, 1490-1496.
34. Fraser, G.; Smith, C. A.; Imrie, K.; Meyer, R. Alemtuzumab in chronic lymphocytic leukemia. Curr. Oncol. 2007, 14, 96-109.
35. Adams, J.; Kauffman, M. Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest. 2004, 22, 304-311.
36. Druker, B. J.; Lydon, N. B. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J. Clin. Invest. 2000, 105, 3-7.
37. Fry, D. W. Inhibition of the epidermal growth factor receptor family of tyrosine kinases as an approach to cancer chemotherapy: Progression from reversible to irreversible inhibitors. Pharmacal. Ther. 1999, 82, 207-218.
38. Savage, P.; Mahmoud, S. Development and economic trends in cancer therapeutic drugs: a 5-year update 2010-2014. Br. J. Cancer 2015, 112, 1037-41.
39. Manning, G.; Whyte, D. B.; Martinez, R. ; Hunter, T. ; Sudarsanam, S. . The Protein Kinase Complement of the Human Genome. Science 2002, 298, 1912-1934.
40. Liu, Y; Gray, N. S. Rational design of inhibitors that bind to inactive kinase conformations. Nat. Chem. Biol. 2006, 2, 358-364.
41. Laufer, S. A.; Domeyer, D. M.; Scior, T. R. F.; Albrecht, W.; Hauser, D. R. J. Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors. J. Med. Chem. 2005, 48, 710-722.
42. Wu, P.; Nielsen, T. E.; Clausen, M. H. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol. Sci. 2015, 36, 422-439.
43. 美國食品藥品監督管理局 U.S. Food and Drug Administration Home Page : http://www.fda.gov/Drugs/default.htm.
44. Hartwell, L. H.; Culotti, J. ; Reidt, B. Genetic control of the cell-division cycle in Yeast, I. detection of mutants. Proc. Natl. Acad. Sci. 1970, 66, 352-359.
45. Morgan, D. O. The Cell Cycle: Principles of Control. 1st ed.; New Science Press: London, 2007.
46. Lapenna, S.; Giordano, A. Cell cycle kinases as therapeutic targets for cancer. Nat. Rev. Drug Discov. 2009, 8, 547-66.
47. Deshpande, A.; Sicinski, P.; Hinds, P. W. Cyclins and cdks in development and cancer: a perspective. Oncogene 2005, 24, 2909-2915.
48. Canavese, M.; Santo, L.; Raje, N. Cyclin dependent kinases in cancer: potential for therapeutic intervention. Cancer Biol. Ther. 2012, 13, 451-457.
49. Francisco, L.; Wang, W. F.; Chan, C. S. M. Type 1 Protein Phosphatase Acts in Opposition to Ipll Protein Kinase in Regulating Yeast Chromosome Segregation. Mol. Cell. Biol. 1994, 14, 4731-4740.
50. Glover, D. M.; Leibowitz, M. H.; McLean, D. A.; Parry, H. Mutations in aurora Prevent Centrosome Separation Leading to the Formation of Monopolar Spindles. Cell 1995, 81, 95-105.
51. Keen, N.; Taylor, S. Aurora-kinase Inhibitors as anticancer agents. Nat. Rev. 2004, 4, 927-936.
52. Vader, G.; Lens, S. M. The Aurora kinase family in cell division and cancer. Biochim. Biophys. Acta 2008, 1786, 60-72.
53. Pollard, J. R.; Mortimore, M. Discovery and development of Aurora kinase inhibitors as anticancer agents. J. Med. Chem. 2009, 52, 2639-2651.
54. Cheung, C. H. A.; Coumar, M. S.; Hsieh, H. P.; Chang, J. Y. Aurora kinase inhibitors in preclinical and clinical testing. Expert Opin. Investig. Drugs 2009, 18, 379-398.
55. Carmena, M.; Earnshaw, W. C. The cellular geography of Aurora kinases. Nat. Rev. Mol. Cell Biol. 2003, 4, 842-854.
56. Bernard, M.; Sanseau, P.; Henry, C.; Couturier, A. ; Prigent, C. Cloning of STK13, a third human protein kinase related to Drosophila Aurora and budding yeast Ipl1 that maps on chromosome 19q13.3–ter. Genomics 1998, 53, 406-409.
57. Sasai, K.; Katayama, H.; Stenoien, D. L.; Fujii, S.; Honda, R.; Kimura, M.; Okano, Y.; Tatsuka, M.; Suzuki, F.; Nigg, E. A.; Earnshaw, W. C.; Brinkley, W. R.; Sen, S. Aurora-C kinase is a novel chromosomal passenger protein that can complement Aurora-B kinase function in mitotic cells. Cell Motil. Cytoskeleton 2004, 59, 249–263.
58. Sen, S.; Zhou, H.; White, R. A. A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplifed and overexpressed in human breast cancer cell lines. Oncogene 1997, 14, 2195-2200.
59. Bischoff, J. R.; Anderson, L.; Zhu, Y.; Mossie, K.; Ng, L.; Souza, B.; Schryver, B.; Flanagan, P.; Clairvoyant, F.; Ginther, C.; Chan, C. S. M.; Novotny, M.; Slamon, D. J.; Plowman, G. D. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 1998, 17, 3052–3065.
60. Li, J. J.; Li, S. A. Mitotic kinases: the key to duplication, segregation, and cytokinesis errors, chromosomal instability, and oncogenesis. Pharmacol. Ther. 2006, 111, 974-984.
61. Goldenson, B.; Crispino, J. D. The aurora kinases in cell cycle and leukemia. Oncogene 2015, 34, 537-545.
62. Choudary, I.; Barr, P. M.; Friedberg, J. Recent advances in the development of Aurora kinases inhibitors in hematological malignancies. Ther. Adv. Hematol. 2015, 6, 282-294.
63. Harrington, E. A.; Bebbington, D.; Moore, J.; Rasmussen, R. K.; Ajose-Adeogun, A. O.; Nakayama, T.; Graham, J. A.; Demur, C.; Hercend, T.; Diu-Hercend, A.; Su, M.; Golec, J. M.; Miller, K. M. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat. Med. 2004, 10, 262-267.
64. Cheetham, G. M.; Charlton, P. A.; Golec, J. M.; Pollard, J. R. Structural basis for potent inhibition of the Aurora kinases and a T315I multi-drug resistant mutant form of Abl kinase by VX-680. Cancer Lett. 2007, 251, 323-329.
65. Fancelli, D. ; Berta, D; Bindi, S. ; Cameron, A. ; Cappella, P.; Carpinelli, P.; Catana, C.; Forte, B. ; Giordano, P.; Giorgini, M. L.; Mantegani, S. ; Marsiglio, A.; Meroni, M.; Juergen Moll, Valeria Pittala; Roletto, F.; Severino, D.; Soncini, C. ; Storici, P.; Tonani, R. ; Varasi, M.; Vulpetti, A.; Vianello, P. Potent and selective aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition. J. Med. Chem. 2005, 48, 3080-3084.
66. Fancelli, D.; Moll, J.; Varasi, M.; Bravo, R.; Artico, R.; Berta, D.; Bindi, S.; Cameron, A.; Candiani, I.; Cappella, P.; Carpinelli, P.; Croci, W.; Forte, B.; Giorgini, M. L.; Klapwijk, J. ; Marsiglio, A.; Pesenti, E.; Rocchetti, M.; Roletto, F.; Severino, D.; Soncini, C.; Storici, P.; Tonani, R.; Zugnoni, P.; Vianello, P. 1,4,5,6-Tetrahydropyrrolo [3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J. Med. Chem. 2006, 49, 7247-7251.
67. Soncini, C.; Carpinelli, P.; Gianellini, L.; Fancelli, D.; Vianello, P.; Rusconi, L.; Storici, P.; Zugnoni, P.; Pesenti, E.; Croci, V.; Ceruti, R.; Giorgini, M. L.; Cappella, P.; Ballinari, D.; Sola, F.; Varasi, M.; Bravo, R.; Moll, J. PHA-680632, a novel Aurora kinase inhibitor with potent antitumoral activity. Clin. Cancer Res. 2006, 12, 4080-4089.
68. Howard, S.; Berdini, A. ; Boulstridge, J. A.; Carr, M. G.; Cross, D. M. ; Curry, J.; Devine, L. A.; Early, T. R. ; Fazal, L. ; Gill, A. L. ; Heathcote, M. ; Maman, S. ; Matthews, J. E. ; McMenamin, R. L.; Navarro, E. F.; O’Brien, M. A. ; O’Reilly, M.; Rees, D. C.; Reule, M.; Tisi, D. ; Williams, G.; Vinkovic, M.; Wyatt, P.G. Fragment-Based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent Aurora kinase activity. J. Med. Chem. 2009, 52, 379-388.
69. 美國國家衛生研究院 U.S. National Institutes of Health https://clinicaltrials.gov.
70. Taverna, P.; Hogan, J.; Kumer, J.; Arbitrario, J. P.; Kumer, J. L.; Hoch, U.; Howlett, A. SNS-314, a potent inhibitor of Aurora kinases, shows broad anti-tumor activity and dosing flexibility in vivo. Ann. Oncol. 2007, 18, Abstrac No. 204.
71. Oslob, J. D.; Romanowski, M. J.; Allen, D. A.; Baskaran, S.; Bui, M.; Elling, R. A.; Flanagan, W. M.; Fung, A. D.; Hanan, E. J.; Harris, S.; Heumann, S. A.; Hoch, U.; Jacobs, J. W.; Lam, J.; Lawrence, C. E.; McDowell, R. S.; Nannini, M. A.; Shen, W.; Silverman, J. A.; Sopko, M. M.; Tangonan, B. T.; Teague, J.; Yoburn, J. C.; Yu, C. H.; Zhong, M.; Zimmerman, K. M.; O'Brien, T.; Lew, W. Discovery of a potent and selective aurora kinase inhibitor. Bioorg. Med. Chem. Lett. 2008, 18, 4880-4884.
72. Zhong, M.; Bui, M.; Shen, W.; Baskaran, S.; Allen, D. A.; Elling, R. A.; Flanagan, W. M.; Fung, A. D.; Hanan, E. J.; Harris, S. O.; Heumann, S. A.; Hoch, U.; Ivy, S. N.; Jacobs, J. W.; Lam, S.; Lee, H.; McDowell, R. S.; Oslob, J. D.; Purkey, H. E.; Romanowski, M. J.; Silverman, J. A.; Tangonan, B. T.; Taverna, P.; Yang, W.; Yoburn, J. C.; Yu, C. H.; Zimmerman, K. M.; O'Brien, T.; Lew, W. 2-Aminobenzimidazoles as potent Aurora kinase inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 5158-61.
73. Cee, V. J.; Schenkel, L. B.; Hodous, B. L.; Deak, H. L.; Nguyen, H. N.; Olivieri, P. R.; Romero, K.; Bak, A.; Be, X.; Bellon, S.; Bush, T. L.; Cheng, A. C.; Chung, G.; Coats, S.; Eden, P. M.; Hanestad, K.; Gallant, P. L.; Gu, Y.; Huang, X.; Kendall, R. L.; Lin, M. H.; Morrison, M. J.; Patel, V. F.; Radinsky, R.; Rose, P. E.; Ross, S.; Sun, J. R.; Tang, J.; Zhao, H.; Payton, M.; Geuns-Meyer, S. D. Discovery of a potent, selective, and orally bioavailable pyridinyl pyrimidine phthalazine aurora kinase inhibitor. J. Med. Chem. 2010, 53, 6368-6377.
74. Payton, M.; Bush, T. L.; Chung, G.; Ziegler, B.; Eden, P.; McElroy, P.; Ross, S.; Cee, V. J.; Deak, H. L.; Hodous, B. L.; Nguyen, H. N.; Olivieri, P. R.; Romero, K.; Schenkel, L. B.; Bak, A.; Stanton, M.; Dussault, I.; Patel, V. F.; Geuns-Meyer, S.; Radinsky, R.; Kendall, R. L. Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. Cancer Res. 2010, 70, 9846-9854.
75. Geuns-Meyer, S.; Cee, V. J.; Deak, H. L.; Du, B.; Hodous, B. L.; Nguyen, H. N.; Olivieri, P. R.; Schenkel, L. B.; Vaida, K. R.; Andrews, P.; Bak, A.; Be, X.; Beltran, P. J.; Bush, T. L.; Chaves, M. K.; Chung, G.; Dai, Y.; Eden, P.; Hanestad, K.; Huang, L.; Lin, M. H.; Tang, J.; Ziegler, B.; Radinsky, R.; Kendall, R.; Patel, V. F.; Payton, M. Discovery of N-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methyl- thiophen-2-yl)phthalazin-1-amine (AMG 900), a highly selective, orally bioavailable inhibitor of Aurora kinases with activity against multidrug-resistant cancer cell lines. J. Med. Chem. 2015, 58, 5189-5207.
76. Fletcher, G. C.; Brokx, R. D.; Denny, T. A.; Hembrough, T. A.; Plum, S. M.; Fogler, W. E.; Sidor, C. F.; Bray, M. R. ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action. Mol. Cancer Ther. 2011, 10, 126-137.
77. Shimomura, T.; Hasako, S.; Nakatsuru, Y.; Mita, T.; Ichikawa, K.; Kodera, T.; Sakai, T.; Nambu, T.; Miyamoto, M.; Takahashi, I.; Miki, S.; Kawanishi, N.; Ohkubo, M.; Kotani, H.; Iwasawa, Y. MK-5108, a highly selective Aurora-A kinase inhibitor, shows antitumor activity alone and in combination with docetaxel. Mol. Cancer Ther. 2010, 9, 157-166.
78. Kollareddy, M.; Zheleva, D.; Dzubak, P.; Brahmkshatriya, P. S.; Lepsik, M.; Hajduch, M. Aurora kinase inhibitors: progress towards the clinic. Invest. New Drugs 2012, 30, 2411-2432.
79. Sells, T. B.; Chau, R.; Ecsedy, J. A.; Gershman, R. E.; Hoar, K.; Huck, J.; Janowick, D. A.; Kadambi, V. J.; LeRoy, P. J.; Stirling, M.; Stroud, S. G.; Vos, T. J.; Weatherhead, G. S.; Wysong, D. R.; Zhang, M.; Balani, S. K.; Bolen, J. B.; Manfredi, M. G.; Claiborne, C. F. MLN8054 and Alisertib (MLN8237): discovery of selective oral Aurora A inhibitors. ACS Med. Chem. Lett. 2015, 6, 630-634.
80. Hauf, S.; Cole, R. W.; LaTerra, S.; Zimmer, C. ; Schnapp, G.; Rainer Walter, R.; Heckel, A.; Meel, J.; Rieder, C. L.; Peters, J. The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore–microtubule attachment and in maintaining the spindle assembly checkpoint. J. Cell Biol. 2003, 161, 281-294.
81. Adams, N. D.; Adams, J. L.; Burgess, J. L.; Chaudhari, A. M.; Copeland, R. A.; Donatelli, C. A.; Drewry, D. H.; Fisher, K. E.; Hamajima, T.; Hardwicke, M. A.; Huffman, W. F.; Koretke-Brown, K. K.; Lai, Z. V.; McDonald, O. B.; Nakamura, H.; Newlander, K. A.; Oleykowski, C. A.; Parrish, C. A.; Patrick, D. R.; Plant, R.; Sarpong, M. A.; Sasaki, K.; Schmidt, S. J.; Silva, D. J.; Sutton, D.; Tang, J.; Thompson, C. S.; Tummino, P. J.; Wang, J. C.; Xiang, H.; Yang, J.; Dhanak, D. Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase. J. Med. Chem. 2010, 53, 3973-4001.
82. Mortlock, A. A.; Foote, K. M. ; Heron, N. M.; Jung, F. H.; Pasquet, G.; Lohmann, J.-J. M.; Warin, N.; Renaud, F.; De Savi, C.; Roberts, N. J.; Johnson, T.; Dousson, C. B.; Hill, G. B.; Perkins, D.; Hatter, G.; Wilkinson, R. W.; Wedge, S. R.; Heaton, S. P.; Odedra, R.; Keen, N. J.; Crafter, C.; Brown, E.; Thompson, K.; Brightwell, S.; Khatri, L.; Kearney, S.; McKillop, D.; Rhead, S.; Parry, T.; Green, S. Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of Aurora B kinase. J. Med. Chem. 2007, 50, 2213-2224.
83. Yang, J.; Ikezoe, T.; Nishioka, C.; Tasaka, T.; Taniguchi, A.; Kuwayama, Y.; Komatsu, N.; Bandobashi, K.; Togitani, K.; Koeffler, H. P.; Taguchi, H.; Yokoyama, A. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood 2007, 110, 2034-2040.
84. Ashford , M. B.; Nolan, III , J. M. ; Shin, E.; Song, Y.; Troiano, G.; Wang, H. Therapeutic polymeric nanoparticles and methods of making and using same. . WO2015036792 A1, 2015.
85. Sarvagalla, S.; Hsieh, H. P.; Coumar, M. S. Therapeutic polymeric nanoparticles and the methods of making and using thereof: a patent evaluation of WO2015036792. Expert Opin. Ther. Pat. 2016, 26.
86. Coumar, M. S.; Wu, J. S.; Leou, J. S.; Tan, U. K.; Chang, C. Y.; Chang, T. Y.; Lin, W. H.; Hsu, J. T.; Chao, Y. S.; Wu, S. Y.; Hsieh, H. P. Aurora kinase A inhibitors: identification, SAR exploration and molecular modeling of 6,7-dihydro-4H-pyrazolo- [1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-dione scaffold. Bioorg. Med. Chem. Lett. 2008, 18, 1623-1627.
87. Coumar, M. S.; Leou, J. S.; Shukla, P.; Wu, J. S.; Dixit, A. K. ; Lin, W. H.; Chang, C. Y.; Lien, T. W. ; Tan, U. K. ; Chen, C. H. ; Hsu, J. T.; Chao, Y. S.; Wu, S. Y.; Hsieh, H. P. Structure-based drug design of novel Aurora kinase A inhibitors: structural basis for potency and specificity. J. Med. Chem. 2009, 52, 1050–1062.
88. Coumar, M. S.; Tsai, M. T.; Chu, C. Y.; Uang, B. J.; Lin, W. H.; Chang, C. Y.; Chang, T. Y.; Leou, J. S.; Teng, C. H.; Wu, J. S.; Fang, M. Y.; Chen, C. H.; Hsu, J. T.; Wu, S. Y.; Chao, Y. S.; Hsieh, H. P. Identification, SAR studies, and X-ray co-crystallographic analysis of a novel furanopyrimidine aurora kinase A inhibitor. ChemMedChem 2010, 5, 255-267.
89. Coumar, M. S.; Chu, C. Y.; Lin, C. W.; Shiao, H. Y.; Ho, Y. L.; Reddy, R.; Lin, W. H.; Chen, C. H.; Peng, Y. H.; Leou, J. S.; Lien, T. W.; Huang, C. T.; Fang, M. Y.; Wu, S. H.; Wu, J. S.; Chittimalla, S. K.; Song, J. S.; Hsu, J. T.; Wu, S. Y.; Liao, C. C.; Chao, Y. S.; Hsieh, H. P. Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification. J. Med. Chem. 2010, 53, 4980-4988.
90. Shiao, H. Y.; Coumar, M. S.; Chang, C. W.; Ke, Y. Y.; Chi, Y. H.; Chu, C. Y.; Sun, H. Y.; Chen, C. H.; Lin, W. H.; Fung, K. S.; Kuo, P. C.; Huang, C. T.; Chang, K. Y.; Lu, C. T.; Hsu, J. T.; Chen, C. T.; Jiaang, W. T.; Chao, Y. S.; Hsieh, H. P. Optimization of ligand and lipophilic efficiency to identify an in vivo active furano-pyrimidine Aurora kinase inhibitor. J. Med. Chem. 2013, 56, 5247-5260.
91. Wu, J. M.; Chen, C. T.; Coumar, M. S.; Lin, W. H.; Chen, Z. J.; Hsu, J. T. A.; Peng, Y. H.; Shiao, H. Y.; Lin, W. H.; Chu, C. Y.; Wu, J. S.; Lin, C. T.; Chen, C. P.; Hsueh, C. C.; Chang, K. Y.; Kao, L. P.; Huang, C. Y. F.; Chao, Y. S.; Wu, S. Y.; Hsieh, H. P.; Chi, Y. H. Aurora kinase inhibitors reveal mechanisms of HURP in nucleation of centrosomal and kinetochore microtubules. Proce. Natl. Acad. Sci. 2013, 110, 1779-1787.
92. Cohen, N. C.; Blaney, J. M.; Humblet, C.; Gund, P. ; Barry, D. C. Molecular modeling software and methods for medicinal chemistry. J. Med. Chem. 1990, 33, 883-894.
93. Ke, Y. Y.; Shiao, H. Y.; Hsu, Y. C.; Chu, C. Y.; Wang, W. C.; Lee, Y. C.; Lin, W. H.; Chen, C. H.; Hsu, J. T.; Chang, C. W.; Lin, C. W.; Yeh, T. K.; Chao, Y. S.; Coumar, M. S.; Hsieh, H. P. 3D-QSAR-assisted drug design: identification of a potent quinazoline-based Aurora kinase inhibitor. ChemMedChem 2013, 8, 136-148.
94. Ke, Y. Y.; Coumar, M. S.; Shiao, H. Y.; Wang, W. C.; Chen, C. W.; Song, J. S.; Chen, C. H.; Lin, W. H.; Wu, S. H.; Hsu, J. T.; Chang, C. M.; Hsieh, H. P. Ligand efficiency based approach for efficient virtual screening of compound libraries. Eur. J. Med. Chem. 2014, 83, 226-235.
95. Wilmes, L. J.; Pallavicini, M. G.; Fleming, L. M.; Gibbs, J.; Wang, D.; Li, K. L.; Partridge, S. C.; Henry, R. G.; Shalinsky, D. R.; Hu-Lowe, D.; Park, J. W.; McShane, T. M.; Lu, Y.; Brasch, R. C.; Hylton, N. M. AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging. Magn. Reson. Imaging 2007, 25, 319-327.
96. Swahn, B. M.; Huerta, F.; Kallin, E.; Malmstrom, J.; Weigelt, T.; Viklund, J.; Womack, P.; Xue, Y.; Ohberg, L. Design and synthesis of 6-anilinoindazoles as selective inhibitors of c-Jun N-terminal kinase-3. Bioorg. Med. Chem. Lett. 2005, 15, 5095-5099.
97. Kusakabe, K.; Ide, N.; Daigo, Y.; Tachibana, Y.; Itoh, T.; Yamamoto, T.; Hashizume, H.; Hato, Y.; Higashino, K.; Okano, Y.; Sato, Y.; Inoue, M.; Iguchi, M.; Kanazawa, T.; Ishioka, Y.; Dohi, K.; Kido, Y.; Sakamoto, S.; Yasuo, K.; Maeda, M.; Higaki, M.; Ueda, K.; Yoshizawa, H.; Baba, Y.; Shiota, T.; Murai, H.; Nakamura, Y. Indazole-based potent and cell-active Mps1 kinase inhibitors: rational design from pan-kinase inhibitor anthrapyrazolone (SP600125). J. Med. Chem. 2013, 56, 4343-4356.
98. Pastor, R. M.; Burch, J. D.; Magnuson, S.; Ortwine, D. F.; Chen, Y.; De La Torre, K.; Ding, X.; Eigenbrot, C.; Johnson, A.; Liimatta, M.; Liu, Y.; Shia, S.; Wang, X.; Wu, L. C.; Pei, Z. Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors. Bioorg. Med. Chem. Lett. 2014, 24, 2448-2452.
99. Laufer, R.; Forrest, B.; Li, S. W.; Liu, Y.; Sampson, P.; Edwards, L.; Lang, Y.; Awrey, D. E.; Mao, G.; Plotnikova, O.; Leung, G.; Hodgson, R.; Beletskaya, I.; Mason, J. M.; Luo, X.; Wei, X.; Yao, Y.; Feher, M.; Ban, F.; Kiarash, R.; Green, E.; Mak, T. W.; Pan, G.; Pauls, H. W. The discovery of PLK4 inhibitors: (E)-3-((1H-Indazol-6-yl)- methylene)indolin-2-ones as novel antiproliferative agents. J. Med. Chem. 2013, 56, 6069-87.
100. Sampson, P. B.; Liu, Y.; Patel, N. K.; Feher, M.; Forrest, B.; Li, S. W.; Edwards, L.; Laufer, R.; Lang, Y.; Ban, F.; Awrey, D. E.; Mao, G.; Plotnikova, O.; Leung, G.; Hodgson, R.; Mason, J. M.; Wei, X.; Kiarash, R.; Green, E.; Qiu, W.; Chirgadze, N. Y.; Mak, T. W.; Pan, G.; Pauls, H. W. The Discovery of Polo-Like Kinase 4 Inhibitors: identification of (1R,2S)-2-(3-((E)-4-(((cis)-2,6-dimethylmorpholino)methyl)styryl)- 1H-indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (CFI-400945) as a potent, orally active antitumor agent. J. Med. Chem. 2015, 58, 130-146.
101. Woods, K. W.; Fischer, J. P.; Claiborne, A.; Li, T.; Thomas, S. A.; Zhu, G. D.; Diebold, R. B.; Liu, X.; Shi, Y.; Klinghofer, V.; Han, E. K.; Guan, R.; Magnone, S. R.; Johnson, E. F.; Bouska, J. J.; Olson, A. M.; de Jong, R.; Oltersdorf, T.; Luo, Y.; Rosenberg, S. H.; Giranda, V. L.; Li, Q. Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors. Bioorg. Med. Chem. 2006, 14, 6832-6846.
102. Miller, R. M.; Paavilainen, V. O.; Krishnan, S.; Serafimova, I. M.; Taunton, J. Electrophilic fragment-based design of reversible covalent kinase inhibitors. J. Am. Chem. Soc. 2013, 135, 5298-5301.
103. Ritzén, Andreas; Sørensen, Morten D.; Dack, Kevin N.; Greve, Daniel R.; Jerre, Anders; Carnerup, Martin A.; Rytved, Klaus A.; Bagger-Bahnsen, Jesper. Fragment-based discovery of 6-arylindazole JAK inhibitors. ACS Med. Chem. Lett. 2016, 7, 641-646.
104. Goodman, K. B.; Cui, H.; Dowdell, S. E.; Gaitanopoulos, D. E.; Ivy, R. L.; Sehon, C. A.; Stavenger, R. A.; Wang, G. Z. ; Viet, A. Q.; Xu, W.; Ye, G.; Semus, S. F.; Evans, C.; Fries, H. E.; Jolivette, L. J.; Kirkpatrick, R. B.; Dul, E.; Khandekar, S. S.; Yi, T.; Jung, D. K.; Wright, L. L. ; Smith, G. K.; Behm, D. J.; Bentley, R.; Doe, C. P.; Hu, E.; Dennis Lee, D. Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors. J. Med. Chem. 2007, 50, 6-9.
105. Dai, Y.; Hartandi, K.; Ji, Z.; Ahmed, A. A.; Albert, D. H.; Bauch, J. L.; Bouska, J. J.; Bousquet, P. F.; Cunha, G. A. ; Glaser, K. B.; Harris, C. M.; Hickman, D.; Guo, J.; Li, J.; Marcotte, P. A.; Marsh, K. C.; Moskey, M. D.; Martin, R. L.; Olson, A. M.; Osterling, D. J.; Pease, L. J.; Soni, N. B.; Stewart, K. D.; Stoll, V. S.; Tapang, P.; Reuter, D. R.; Davidsen, S. K.; Michaelides, M. R. Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5- methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor. J. Med. Chem. 2007, 50, 1584-1597.
106. Liu, J.; Peng, X.; Dai, Y.; Zhang, W.; Ren, S.; Ai, J.; Geng, M.; Li, Y. Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold. Org. Biomol. Chem. 2015, 13, 7643-7654.
107. Furlotti, G.; Alisi, M. A.; Cazzolla, N.; Dragone, P.; Durando, L.; Magaro, G.; Mancini, F.; Mangano, G.; Ombrato, R.; Vitiello, M.; Armirotti, A.; Capurro, V.; Lanfranco, M.; Ottonello, G.; Summa, M.; Reggiani, A. Hit optimization of 5-Substituted-N- (piperidin-4-ylmethyl)-1H-indazole-3-carboxamides: Potent glycogen synthase kinase-3 (GSK-3) inhibitors with in Vivo activity in model of mood disorders. J. Med. Chem. 2015, 58, 8920-8937.
108. Down, K.; Amour, A.; Baldwin, I. R.; Cooper, A. W.; Deakin, A. M.; Felton, L. M.; Guntrip, S. B.; Hardy, C.; Harrison, Z. A.; Jones, K. L.; Jones, P.; Keeling, S. E.; Le, J.; Livia, S.; Lucas, F.; Lunniss, C. J.; Parr, N. J.; Robinson, E.; Rowland, P.; Smith, S.; Thomas, D. A.; Vitulli, G.; Washio, Y.; Hamblin, J. N. Optimization of novel indazoles as highly potent and selective inhibitors of phosphoinositide 3-kinase δ for the treatment of respiratory disease. J. Med. Chem. 2015, 58, 7381-7399.
109. Zhao, G.; Li, W. Y.; Chen, D.; Henry, J. R.; Li, H. Y.; Chen, Z.; Zia-Ebrahimi, M.; Bloem, L.; Zhai, Y.; Huss, K.; Peng, S. B.; McCann, D. J. A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol. Cancer Ther. 2011, 10, 2200-2210.
110. Liao, J. J. Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J. Med. Chem. 2007, 50, 409-424.
111. Liu, Y. ; Gray, N. S. Rational design of inhibitors that bind to inactive kinase conformations. Nat. Chem. Biol. 2006, 2, 358-364.
112. Yan, A.; Wang, L.; Xu, S.; Xu, J. Aurora-A kinase inhibitor scaffolds and binding modes. Drug Discov. Today 2011, 16, 260-269.
113. Glickman, J. F. Assay development for protein kinase enzymes. In Assay Guidance Manual, 2012.
114. Riss, T. L.; Moravec, R. A.; Niles, A. L.; Benink, H. A.; Worzella, T. J.; Minor, L. Cell viability assays. In Assay Guidance Manual 2013.
115. Chiang, C. C.; Lin, Y. H.; Lin, S. F.; Lai, C. L.; Liu, C.; Wei, W. Y.; Yang, S. C.; Wang, R. W.; Teng, L. W.; Chuang, S. H.; Chang, J. M.; Yuan, T. T.; Lee, Y. S.; Chen, P.; Chi, W. K.; Yang, J. Y.; Huang, H. J.; Liao, C. B.; Huang, J. J. Discovery of pyrrole-indoline-2-ones as Aurora kinase inhibitors with a different inhibition profile. J. Med. Chem. 2010, 53, 5929-5941.
116. Khanwelkar, R. R.; Chen, G. S.; Wang, H. C.; Yu, C. W.; Huang, C. H.; Lee, O.; Chen, C. H.; Hwang, C. S.; Ko, C. H.; Chou, N. T.; Lin, M. W.; Wang, L. M.; Chen, Y. C.; Hseu, T. H.; Chang, C. N.; Hsu, H. C.; Lin, H. C.; Shih, Y. C.; Chou, S. H.; Tseng, H. W.; Liu, C. P.; Tu, C. M.; Hu, T. L.; Tsai, Y. J.; Chern, J. W. Synthesis and structure-activity relationship of 6-arylureido-3-pyrrol-2-ylmethylideneindolin-2-one derivatives as potent receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. 2010, 18, 4674-4686.
117. Kumar, J. S. D; Ho, M. M. ; Toyokuni, T. Simple and chemoselective reduction of aromatic nitro compounds to aromatic amines: reduction with hydriodic acid. Tetrahedron Lett. 2001, 42, 5601-5603.
118. Laufer, R.; Pauls, H. W.; Feher, M.; Ng, G.; Liu, Y.; Edwards, L. G.; Patel, N. K. B.; Pan, G.; Mak, T. W. Kinase inhibitors and method of treating cancer with same. WO 2011123937 A1, 2011.
119. Kerns, E. H.; Di, L. Pharmaceutical profiling in drug discovery. Drug Discov. Today 2003, 8, 316-323.
120. Yang, Y.; Shen, Y.; Li, S.; Jin, N.; Liu, H.; Yao, X. Molecular dynamics and free energy studies on Aurora kinase A and its mutant bound with MLN8054: insight into molecular mechanism of subtype selectivity. Mol. Biosyst. 2012, 8, 3049-3060.
121. Guo, Q.; Feng, L. S.; Liu, M. L.; Zhang, Y. B.; Chai, Y.; Lv, K.; Guo, H. Y.; Han, L. Y. Synthesis and in vitro antibacterial activity of fluoroquinolone derivatives containing 3-(N'-alkoxycarbamimidoyl)-4-(alkoxyimino) pyrrolidines. Eur. J. Med. Chem. 2010, 45, 5498-5506.