抑制腫瘤細胞轉移和成長的分子靶向性先導藥物研發(Ⅳ)---先導抗癌標靶藥物nstpbp253和355的最佳化設計和新穎奈米化抑制腫瘤藥物傳輸配方

Abstract

我們從先導藥物#1250更改為#194延續實驗至今，持續修飾化合物結構以及利用適當配方技術增加溶解度以及提高藥物功能。終於在今年我們在改變#194結構之衍生物NCTU-Sun-253的生物活性上得到突破性的結果，#253類的衍生物尤其是在溶解度以及對tumor size的影響都有顯著的提昇，且抑制活性趨近於以上市藥物sutent以及Sorafenib。 在溶解度方面253類的衍生物幾乎是194的100倍，我們也試著改變化合物的結構來提高抑制血管新生因子的活性和溶解度。藉由更改R1、R2、R3、R4的取代基以及雜原子，我們已經利用微波式組合化學合成一系列的253衍生物，並將這些分子送給郭教授篩選。並且曾宇鳳博士利用了VEGFR-2的蛋白質結構及VEGFR-3蛋白質序列模擬出VEGFR-3的蛋白質結構，我們將NCTU-Sun-253之結構送給曾博士計算與VEGFR-3結合的情形，運用曾博士的計算結果及預測，合成出一系列可能具有活性的化合物，並將NCTU-Sun-253化學結構優化到最佳的結果，成為未來開發更具活性的VEGFR-3抑制劑重要的依據; 由於這些令人振奮結果，我們預計很快的就可以完成臨床前的實驗 。

Interest in novel target-directed cancer drugs extends from basic research scientists to practicing oncologists. Recently, many heterocyclic compounds are widely exploited as ‘lead’ in cancer drug design as the protein kinase inhibitors. An extension of the initial contribution in molecular oncology, our research progress will move more effectively through an appreciation of previous results. We herein disclose a novel chemical series of bis-heterobicyclic compounds #194, #253 and heterotricyclic compounds #355 as inhibitors of VEGFR-2 and VEGFR-3 kinase receptors. All these compounds are implicated in angiogenesis and lymphangiogenesis. In previous results we found that the inhibition ability of compound #194 toward VEGFR-3 is much better than compound #1250. However, these compounds have poor water solubility. As a result further development of these compounds into drug candidates was hampered. In order to overcome this issue, we have synthesized the various analogs of #194 with chemical modification in parent structure to improve the aqueous solubility. The collaborative work with Dr. Shih-Kuan Wu has also achieved the little success in this arena through the formulations of corresponding compound to increase the water solubility. The other pharmacokinetic and toxicity studies are under progress for the above compounds. The collaboration with Dr. Yu-Feng Zeng was also greatly helped to construct four-dimensional (4D) quantitative structure-activity relationship (QSAR) model for in silico screening of #253 analogues. Further analysis of the performance and external predictivities proves that this method could provide an efficient inhibition model. By using VEGFR3 activity screening platform, we found compound #253 (IC50: 150 nM) with higher activity than 194-A on inhibition of VEGFR3. It also exhibits greater suppression effect in tube formation assay. Similar to the efficacy of Sorafenib on suppressing tumor growth, #253 dramatically attenuated the growth of VEGFR3-overexpressing (4T1) tumors in vivo. We have improved the solubility of #253 up to 10 mg/ml. In vivo anti-tumor assay shows that Sun#253 treatment (50mg/kg/day；po) decreases the VEGFR3+ breast cancer cell line 4T1 of tumor growth is better than the 194-A. In addition, we also found that growth inhibition of sun #253 on VEGFR3+ lung cancer cell lines CL1-5 and A549 are comparable to that of Sorafenib. Recently, we succeed in non-GLP toxicity tests of #253 by using iv injection of 10mg/kg with different delivery methods for inhibition of tumor growth. With this success, we are planned to analyze inhibiting tumor growth and angiogenesis in breast cancer by #253 as well as toxicity test in animal. In addition, it will be interesting to test the inhibitory effect of #350 and its derivatives on tumor growth, metastasis and angiogenesis in different cancer types. Next we will focus to generate lead compound from the derivatives of #253 and #355 compounds, for the treatment of cancer to achieve better activity than the current drugs such as Sorafenib and Sutent. In future we planned for design and syntheses of different analogs of #253 and #350 compounds followed by in vivo screening of these analogs against different cancer types along with pharmacokinetic studies to make them drug like candidates.