肺癌在全世界各地屬最致命的癌症，又因發病時症狀不明顯，病患確診時期通常都為晚期，因此了解癌症相關進程機制為目前藥物開發中重要的一環。泛素化 (Ubiquitination)的過程中則是將泛素結合在目標的蛋白上，以利特定的蛋白質藉由26S蛋白酶體 (26S Proteasomes）進行降解或是對其目標蛋白質進行活性調控。去泛素化酵素 (Deubiquitinases)功能為自目標蛋白移除泛素。在先前研究中，我們致力於探討泛素特異性胜肽酶二十四在肺癌進程中所扮演的角色，在本研究中，可先看到USP24會正向調控產生抗藥性的肺癌細胞株。並在探討其機制過程中發現，USP24會藉由穩定ABC 轉運蛋白 (ABC transporter)中的 P-gp (P-glycoprotein)及其相關蛋白質-Ezrin進而增加治療藥物的排出。接著，利用結構模擬的方式，去篩選可能成為USP24 抑制劑的化合物，而本篇提供兩種USP24小分子抑制劑，USP24-i1和USP24-i2，其可以抑制USP24的酵素活性及抑制肺癌細胞的轉移活性並抑制化療藥物產生的抗藥性。目前動物實驗正在進行當中，藥物抗藥性在現今癌症治療中為一項很大的課題，有鑑於我們目前的研究，我們認為USP24小分子抑制劑- USP24-i1和USP24-i2非常有潛力發展成為抑制抗藥性產生之臨床藥物所使用。

Lung cancer has been the worldwide leading cause of cancer death. Due to nearly no symptoms and most patients are often diagnosed late, understanding the mechanism of cancer is important for drug development. Ubiquitination is conjugated to target proteins for degradation by 26S-proteasome. Deubiquitinases (DUBs) removing ubiquitin from target proteins have recently recognized as key regulators in plenty of processes from gene transcription to protein degradation also in cell division. Ubiquitin-specific peptidase 24 (USP24) belongs to deubiquitinating families and regulates protein deubiquitination. In previous studies, we clarify multiple roles of USP24 in lung cancer progression. Although the development of lung cancer treatment has improved in these several decades, some patients still suffer from resistant to cancer therapy treatment. In this study, we found that USP24 positive regulated drug resistance in lung cancer cells. The molecular studies found that USP24 increased pumping out the drug by stabilizing ABC transporter, Ezrin and P-gp. Next, we used structure-based strategy to screen the candidates of USP24 inhibitor, and used in vivo and in vitro experiments to study the effect of the USP24 inhibitors. Two USP24 inhibitors, USP24-i1 and USP24-i2, were found to be able to inhibit enzyme activity of USP24, metastasis activity of lung cancer cells, and chemotherapy-induced drug resistance. Drug resistance is a vital issue in various cancer therapy, such as chemotherapy, target therapy and immunotherapy. To develop the useful drug to delay or overcome the drug resistance during cancer therapy is very important. USP24-i1 and USP24-i2, are potential to be developed as the clinical-used drug for conquering drug resistance in the future.

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