标题: 抑制肿瘤细胞转移和成长的分子靶向性先导药物研发---杂环类先导药物的演化和多样式的设计合成(总计画暨子计画一)
Discovery and Development of VEGFR3 Inhibitors as the Targeted Cancer Therapies
作者: 孙仲铭
SUN CHUNG-MING
国立交通大学应用化学系(所)
关键字: 肿瘤新生血管增生;肿瘤淋巴管增生;组合式微波化学;先导药物最佳化;lymphangiogenesis,combinatorial chemistry,lead optimization;microwaveaccelerated chemistry
公开日期: 2007
摘要: 本计划延续之前第二期计画的成果,发现代号Nstpbp001250 化
合物进入临床前之抗癌动物实验,以口服方式给予药剂,委托泛球公
司(MDL)代为测试,测试结果发现Nstpbp001250 对于VEGFR-3 具有专
一的抑制性,而且没有一般抗癌药物强烈细胞的细胞毒性,此药物可
以有效的抑制癌细胞的淋巴管增生,进而阻止癌细胞藉着利用淋巴管
增生转移到远端的器官,这个有机小分子具有一个全新的化学结
构,目前已经申请美国专利,并希望能在本次第三期将研究成果落
实于产业界中。
组合式化学在前驱药物的最佳化上,明显的呈现优势。利用具生
物活性的先导药物分子前驱药为主体,合成各种具有多样取代基之产
物,藉着改变取代基上的官能基,产生各种不同组合的化合物,进而
有效率的建立化学分子库,再经由高通量筛选出具有药理活性的化合
物,提供作为临床前之测试。目前我们已经利用这种新的策略,找到
全新化学结构的Nstpbp001250 化合物,在本计划中,将以此先导药
物做为基本的模板,进行化学分子结构的最佳化,同时进行对于
Nstpbp001250 化合物进行结构和活性之间的关系研究,试图对其结
构进行最佳化以期望能找出更具有活性和选择性的结构,去年我们成
功的合成并发现另一有机小分子Nstpbp00194 比Nstpbp001250 有近
十倍的活性,未来更进一步的,我们将透过与其他结构生物学的实验
室合作(如同步幅射中心的陈俊荣博士),尝试利用Nstpbp001250 化
学小分子和VEGFR-3 蛋白受体的共同结晶来清楚瞭解受体和药物之
间的作用机制,并试图利用其在活性位置的作用机制找寻其他更有效
的抑制抗癌细胞转移的药物。
Vascular endothelial growth factors (VEGFs) and their respective family of
receptor tyrosine kinases (VEGFRs) are key proteins modulating angiogenesis, the
formation of new vasculature from an existing vascular network. Potent, specific,
and non-toxic inhibitors of angiogenesis are powerful clinical tools in oncology and
ophthalmology. Signal blockade via VEGF receptors such as VEGFR-1 and
VEGFR-2 leads to an inhibition of malignant angiogenesis.
Recent report (Cancer Res. 2005, 65, 4389) describing small-molecule inhibitors
affect VEGFR signaling by directly competing with the ATP-binding site of
corresponding intracellular kinase domains. This cause leads to the inhibition of
VEGFR phosphorylation and ultimately to the apoptotic death of the aberrant
endothelial cells. In addition, VEGF-C played an important role in
lymphangiogenesis via a mechanism of activating VEGF receptor 3 (VEGFR-3).
VEGFR-3 has been proposed as a specific marker for lymphatic endothelial cells.
Recent studies indicated that VEGFR-3 also expressed in a variety of human
malignancies, including lung adenocarcinoma, colorectal adenocarcinoma, head and
neck carcinoma, neuroblastoma, and Kaposi's sarcoma. The novel compound
Nstpbp00194 was designed and identified in our laboratory last year, which is able to
compete VEGF-C for VEGFR-3 to act as an antagonist. This compound is found
more ten times more potent than lead compound Nstpbp001250.
Combinatorial chemistry is revolutionizing the process of drug discovery with
outstanding properties. While the traditional principle focuses on the synthesis of
one compound at a time, the novel combinatorial methodologies aim at the
identification of one or a few very promising candidates through the parallel or
mixture-based synthesis and screening of a multitude of compounds. Using this
technique, we discovered a unique, potent lead molecule-Nstpbp001250 within one
year. A general method of rapidly synthesizing analogues of 1250 scaffold would be
greatly advantageous and warrants further investigation for drug discovery. In order
to improve the antitumor profile of parent molecules, it is necessary to perform
various synthetic modifications around the scaffolds. To further application,
co-crystallization of VEFGR-3 with #1250 compound will be proceeded. Libraries
compose of a diverse set of compounds can be possibly produced according to
X-structure of co-crystallization. We will use in vitro screening software such as
Cerius and Catalyst from MSI to design more focusing libraries, which exhibit the
required diversity because effective design of the libraries could reduce the number of
molecules made and tested without reducing their diversity.
官方说明文件#: NSC96-2323-B009-001
URI: http://hdl.handle.net/11536/103031
https://www.grb.gov.tw/search/planDetail?id=1418432&docId=252990
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