研發與生物驗證新穎性MAP4K4小分子抑制劑應用於胰臟癌之治療

Taipei Medical University Institutional Repository > 藥學院 > 新藥研發產業博士學位學程 > 博碩士論文 > Item 987654321/63216

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題名:	研發與生物驗證新穎性MAP4K4小分子抑制劑應用於胰臟癌之治療 Discovery and biological evaluation of novel small molecule inhibitors against MAP4K4 for pancreatic cancer treatment
作者:	張兆締 CHANG, CHAO-DI
貢獻者:	新藥研發產業博士學位學程潘秀玲
關鍵詞:	MAP4K4;JNK傳遞路徑;胰臟癌;以結構為基礎之藥物篩選策略 MAP4K4;JNK signaling pathway;Pancreatic cancer;Structure-based virtual screening
日期:	2023-01-12
上傳時間:	2023-12-07 09:58:59 (UTC+8)
摘要:	手術切除合併化學治療是目前面對胰臟癌主要的治療方式。然而，多數胰臟癌病患因為其腫瘤特性無法有效利用手術切除患部，而化學治療藥物針對晚期癌症效果有限且會產生較強之副作用，因此，設計能可以專一針對癌細胞之標靶治療不僅可以有效抑制腫瘤生長並將可以減少非預期的副作用產生。磷酸? MAP4K4 (mitogen-activated protein kinase kinase kinase kinase 4) 已經被證實在與促進胰臟癌發展有著重要的角色。MAP4K4透過直接磷酸化下游蛋白MKK4以及接續活化 c-Jun N-terminal kinase (JNK)訊息傳遞路徑，進而促進細胞增生相關蛋白的產生。本篇論文旨在以蛋白質結構為基礎之虛擬藥物篩選平台篩選出高選擇性MAP4K4抑制劑 F389-0167，其MAP4K4 酵素活性抑制效果 IC50 為 275.6 nM，再以此結構為基礎，篩選相結構相似化合物，結果顯示 F389-0746 具有更強 MAP4K4 活性抑制能力，其 IC50 數值低為 120.7 nM，進一步分析化合物對於 MAP4K4 之選擇性，F389-0746呈現表現出高選擇性抑制 MAP4K4 活性，在人類胰臟癌細胞實驗中，F389-0746 透過抑制 MAP4K4 訊息傳遞，包括減少 MKK4、JNK、c-Jun磷酸化以控制癌細胞生長並且促進細胞凋亡。此外，而在胰臟癌小鼠異體移植實驗中，F389-0746 亦展現出與化療藥物 gemcitabine 相似之腫瘤生長抑制效果，以上結果皆顯示，F389-0746 具有進一步發展為新穎性胰臟癌治療藥物之潛力。 Pancreatic cancer is a serious and often deadly disease, with a five-year survival rate of less than 15%. Surgery and chemotherapy are currently the most common treatments for pancreatic cancer, but these treatments are not effective and cause unpleasant side effects, particularly at advanced stages of the disease. MAP4K4, a member of MAP4Ks, was found to be associated with tumorigenesis and the development of pancreatic cancer. Overexpressed MAP4K4 was correlated with poor clinical outcomes in pancreatic cancer patients. MAP4K4 phosphorylates MKK4 and further activates JNK signaling pathway to translate proteins, promoting cell proliferation, cell apoptosis, and survival. Therefore, inhibiting MAP4K4 activity in pancreatic tumors is a new therapeutic strategy. Herein, a structure-based virtual screening approach was used to identify potential MAP4K4 inhibitors. The top-ranked compounds were validated using enzyme-based assays, and one compound, F389-0746, was found to be a highly selective MAP4K4 inhibitor with an IC50 of 120.7 nM. A SAR analysis was performed on analogs of the MAP4K4 inhibitor F389-0746. This analysis revealed both favorable and unfavorable sites on the analogs. Moreover, the results of the kinase profiling showed that F389-0746 was highly selective to MAP4K4, indicating that it may have a more targeted effect on this enzyme and may be less likely to cause side effects. In vitro experiments using pancreatic cancer cell lines showed that F389-0746 significantly suppressed cancer cell growth and viability and led to apoptosis by inhibiting the phosphorylation of several proteins in the JNK signaling pathway. Furthermore, the pancreatic xenograft mouse model showed that F389-0746 was able to inhibit tumor growth to a similar extent as the positive control group treated with the chemotherapy drug Gemcitabine. These results suggest that F389-0746 may have promising potential as a novel treatment for pancreatic cancer, and further research is needed to explore its safety and efficacy in clinical trials.
描述:	博士指導教授:潘秀玲委員:皇甫維君委員:許凱程委員:楊家榮委員:黃聰龍委員:潘秀玲
資料類型:	thesis
顯示於類別:	[新藥研發產業博士學位學程] 博碩士論文

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