組織蛋白酶S為一種溶酶體半胱胺酸蛋白酶，主要由免疫系統表達，其在抗原呈現過程中參與降解第二型組織相容性複合體中恆定鏈的角色。研究發現，過度表達之組織蛋白酶S與一些自體免疫疾病有所關連，如：類風濕性關節炎、乾癬等。最近科學家亦發現，組織蛋白酶S會在惡性腫瘤細胞中被過度表達，且在腫瘤細胞的侵襲及轉移上扮演著重要的角色，經由抑制劑阻斷組織蛋白酶S之生物活性以達到癌症治療之構想成為近年藥物開發的新方法。
我們以組織蛋白酶S的水解機制為基礎，設計並合成了16個α-酮醯胺結構之胜肽抑制劑，期望能專一性地抑制目標蛋白酶S進而阻斷癌細胞增長與侵襲的功能。實驗結果發現13個化合物之Ki值低於10 nM，其中有5個抑制活性甚至在pM濃度範圍。其中，我們挑選化合物27c進行動物實驗之研究，結果顯示此化合物不但能有效抑制癌細胞之成長，亦提升了老鼠實驗組之存活率。
另外，為能增加化合物之生物口服利用率及循環時間以達到更優良之藥物療效，我們合成了具四級胺結構之化合物65及1,2,3-三氮唑結構之類肽化合物86、89。上述三個化合物仍保有Ki在奈米濃度等級之抑制活性。未來將進一步進行藥物動力學實驗以探討其發展為抗癌藥物之潛力。

Cathepsin S, a lysosomal cysteine protease, is primarily secreted from immune system and plays a major role in antigen presentation through degradation of invariant chain that is associated with the major histocompatibility class II complex (MHC II). Thus, cathepsin S is related to autoimmune diseases such as rheumatoid arthritis and psoriasis. Recently, scientists also found that cathepsin S is highly expressed in malignant cancer cells and plays an important role in cancer cells invasion, migration, and metastasis. Interruption of its activity by inhibitors has been extensively evaluated as a new therapeutic approach for cancer treatment.
On the basis of cathepsin S proteolytic mechanism, 16 peptidic α-ketoamide inhibitors were designed and synthesized for specifically targeting cathepsin S and suppressing its functions in tumor progression. Results revealed that 13 compounds with Ki values lower than 10 nM and 5 of them even provide picomolar range inhibition activity. Among them, compound 27c was selected for further animal experiment and the results showed obvious inhibition of tumor cell progression and increase of the survival rate.
To further improve oral bioavailability and long circulation half-life of the synthesized compound in medicinal application, compound 65 with quaternary ammonium group and peptidomometics compounds 86 and 89 with 1,2,3-triazole group were successfully synthesized. All of these compounds remain nanomolar scale inhibition activity. We are studying their pharmacokinetics and exploring their potentials as anticancer drugs.

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