2020-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/653560摘要：有別於傳統的小分子酵素抑制劑，只能1對1可逆或不可逆地抑制酵素活性，本實驗室將打造一個小分子藥物促進標靶蛋白質分解平台，首先將設計與合成選擇性多元胺去乙醯&#37238; (polyamine deacetylase, PDAC)抑制劑，並在酵素與細胞層級確定活性後，再利用標靶蛋白降解技術(proteolysis targeting chimera ,PROTAC) 的設計架構，將前述所得的PDAC抑制劑套用上，打造出可以1對多降解多元胺去乙醯&#37238; (PDAC)化合物 PDAC-PROTAC，並優化其口服吸收效率。目前已知在癌症治療後，PDAC的大量表現將誘發細胞自噬 (Autophagy)的保護機制，將保護神經母細胞瘤等等的癌細胞度過癌症治療所帶給細胞的生存壓力，所以配合其他藥物治療，PDAC-PROTAC預期將可以有效減緩其他藥物產生的抗藥性。<br> Abstract: In contrast to traditional small molecule enzyme inhibitors which only inhibit target enzyme one-on-one, our lab is going to develop a small molecule based target protein degradation platform. In the beginning, selective PDAC (polyamine deacetylase) inhibitors will be designed and synthesized, and their enzyme and cell based bioactivity will be evaluated. After generating the selective inhibitors, the PDAC inhibitors will be further transformed to PROTAC based small molecules to give PDAC-PROTAC which could induce many PDAC degradation by one molecule. The oral bioavailability of PDAC-PROTAC will be also optimized. After conventional cancer therapy, PDAC will be over expressed to induce autophagy as a protecting mechanism to protect cancer cells such as neuroblastoma under stress condition brought by cancer therapy. Therefore, PDAC-PROTAC combing with other anticancer drug is expected to effectively to reduce drug resistance in cancer.抗癌小分子蛋白降解anticancersmall moleculeprotein degradation