臺灣博碩士論文加值系統

癌症是至今為止最致命的疾病之一，每年有超過1000萬人死於癌症。因此，攻剋癌症已是刻不容緩的任務。 隨著過去幾十年化學和生物學的進步，癌症治療的選擇越來越多，而針對蛋白激酶是最有前景的方法之一。蛋白激酶在人體的生物學功能中發揮重要作用，包括腫瘤細胞的發育。據文獻指出，絲裂原活化蛋白激酶 (MAP4K4) 與癌症息息相關，例如神經母細胞瘤、大腸直腸癌、前列腺癌和胰腺癌。即便研究清楚指出癌症與MAP4K4的過度表現有關，現行的MAP4K4抑制劑的數量並不多，因而啟發我們進行新穎MAP4K4的設計與合成。 本研究利用基於小片段結構虛擬篩選(Fragment-based virtual screening)，發現了一系列具有 3-(1,2,3,6-四氫吡啶-4-基)-7-氮雜吲哚共同結構的 MAP4K4 抑制劑。我們進行了結構活性關係的研究(SAR)，總共合成了 16 個化合物並完成了體外激酶活性的測定。化合物 10 的激酶 IC50值為 15.8 nM，被發現是所合成化合物中最有效的。這項研究的結果確立了新穎的結構片段作為MAP4K4的抑制劑，帶來良好的結果，並且需要進一步的生物學評估來確定它們作為抗癌製劑。

Cancer is one of the deadliest diseases to date, more than 10 million people die of cancer each year. Therefore, tackling cancer is an imperative task. As advances in chemistry and biology have been made in the past few decades, there have been an increasing amount of treatment options, and targeting protein kinases is one of the promising methods. Protein kinases play a significant role in the biological functions of the human body, including the development of tumor cells. Mitogen-activated protein kinase kinase kinase kinase (MAP4K4) is reported to correlate with a handful of cancers, such as glioblastoma, colorectal cancer, prostate cancer, and pancreatic cancer. Despite the clear correlations between cancer and MAP4K4 overexpression, there is a lack of known inhibitors to date, which intrigued us to develop novel MAP4K4 inhibitors. This study utilizes fragment-based-virtual screening and discovered a series of MAP4K4 inhibitors possessing common structures of 3-(1,2,3,6-tetrahydropyridin-4-yl)-7-azaindoles. A structure-activity relationship (SAR) study was performed, a total of 16 compounds were synthesized and in-vitro kinase assays were completed. Compound 10 possesses a kinase IC50 value of 15.8 nM and was found to be the most potent compound of all. This study established a novel scaffold of MAP4K4 inhibitors, as well as delivered promising results. and will require further biological evaluations to establish them as anti-cancer agents.

Table of Contents
Table of Contents i
Table of Figures ii
Table of Tables iii
Table of Schemes iv
中文摘要 v
Abstract vi
1. Introduction 1
2. Kinase and Kinase inhibitors 3
2.1 Kinases and their relationship with cancer 3
2.2 Development of kinase inhibitors 4
2.3 Why new kinase inhibitors are needed? 5
3. MAP4K4 6
4. Rationale 7
5. Results and Discussion 13
5.1 Chemistry 13
5.2 Biological evaluation 19
6. Conclusion 23
7. Experimental 24
8. References 46
Appendix 53

Table of Figures
Figure 1. Structures of reported MAP4K4 inhibitors 7
Figure 2. The structure of F389-0746 9
Figure 3. The design of compounds 2-16 10
Figure 4. Indole-containing drugs 10
Figure 5. The three binding modes of 7-azaindole 11
Figure 6. FDA approved drugs that contain 7-azaindole 12
Figure 7. The retrosynthetic analysis of compound 23 13
Figure 8. The electrophilic aromatic substitution of azaindole 14

Table of Tables
Table 1. Biological evaluation of synthesized compounds 21

Table of Schemes
Scheme 1. Synthesis of compound 1 15
Scheme 2. Synthesis of compounds 4, 7-9 and 11 16
Scheme 3. Synthesis of compounds 5-6 and 10 16
Scheme 4. Synthesis of compound 2 17
Scheme 5. Synthesis of compound 3 17
Scheme 6. Synthesis of compounds 12 and 13 18
Scheme 7. Synthesis of compounds 14 and 15 19
Scheme 8. Synthesis of compound 16 19

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