Discovery of Novel Microtubule Inhibitors as Potential Anticancer Drugs

微管蛋白是微小管的主要組成分，亦是許多抗有絲分裂劑的重要標的。目前臨床上使用抗有絲分裂劑治療癌症，但常隨著多藥抗藥蛋白的表達，造成藥物抗性而失去療效。因此開發新藥來克服腫瘤的多藥抗藥性，為臨床上刻不容緩的課題。這篇綜論針對近期我們實驗室所研究與開發的新穎微小管抑制劑進行討論。文中所介紹的三個微小管抑制劑，包括一個天然物Salvinal，及兩個合成化合物BPR0Y007與BPR0L075，其乃藉由高通量藥物篩選技術或目標導向藥物設計所開發而來，無論在試管內微管蛋白聚合試驗或癌細胞生長抑制試驗等篩選模式，這三個化合物都具有極佳的抗癌特性。第一個介紹的微小管抑制劑為Salvinal，其由中藥丹參所分離出來，藉由抑制有絲分裂與誘導細胞凋亡來控制腫瘤細胞之生長。第二個介紹的微小管抑制劑為BPR0Y007，其同時扮演DNA拓樸異構酵素I與微小管抑制劑等雙重角色。BPR0Y007能藉由增加Fas(CD95/AP0-l)與p53的表達而快速誘導caspase的活化，進而引起細胞的凋亡。第三個介紹的微小管抑制劑為BPR0L075，其為新穎合成的indole類化合物，屬於CA-4之類似結構，能有效抑制體外或活內的腫瘤細胞生長。BPR0L075能使細胞週期停滯在G2/M期並誘發細胞凋亡，而這些改變，與細胞內調控細胞週期或細胞凋亡的蛋白，包括Bcl-2、cyclin B1、Cdc2和Cdc25c的變化相關。最重要的是，這三個化合物皆不為多藥抗藥蛋白p-gp170/MDR及MRP的受質，故對於各類惡性腫瘤的治療應有極佳的潛力，特別是當癌症病人具有多藥抗藥性也應具有極佳的治療空間。其中，BPR0L075為目前我們藥物開發團隊中最具潛力之候選藥物，並計畫進入第一期臨床試驗。Tubulin, the major protein compound of microtubules, is the target of numerous antimitotic agents. Antimitotic agents have been used clinically to treat patients with neoplastic disease, a major drawback is the loss of efficacy over time because of the development of resistance due to express MDR protein. There is a need for new compounds that are effective in treating drug-resistant tumors. This review article focuses on recent research in our laboratory on the development of novel microtubules inhibitors. Three anti-tubulin compounds, including natural product (Salvinal) and synthetic chemicals (BPR0Y007 and BPR0L075), with potent anti-cancer property, were obtained by high-throughput screening or rational drug design based primarily on in vitro tubulin polymerization and the inhibition of cell proliferation assay. First, Salvinal, a compound isolated from Salvia miltiorrhizae Bunge (Dansen), possesses anti-proliferative activity against various human cancer cells. It is a novel type of microtubule inhibitor against cancer cell growth through mitotic arresting and apoptotic induction. Secondly, BPR0Y007, which is a dual inhibitor of both tubulin and topoisomerase 1 and can induce a rapid caspase activation involving upregulation of Fas (CD95/APO-1) and wild-type p53. Finally, BPR0L075, a novel synthetic indole compound designed from CA-4, is efficacious in suppressing cell growth in a variety of solid tumor models and exhibits significant antitumoral efficacy in vivo. BPR0L075 causes cell cycle arresting in G2/M phase and induces apoptosis that is associated with change in Bcl-2, cyclin Bi, Cdc2 and Cdc25C. These compounds are all poor substrates for transport by Pgp170/MDR and MRP. Thus, they have potential for management of various malignancies, particularly for patients with demonstrated drug resistance. BPR0L075 is now planning to enter the phase I clinical trial, is a current highlight of our drug development program.