作用于Ras/Raf/MEK/ERK信号通路的多靶点抗肿瘤药物的设计、合成及药理活性初筛
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摘要
研究发现在真核细胞中都有Ras/Raf/MEK/ERK信号传导通路,Ras信号通路在细胞的增殖,分化,凋亡,转移,代谢等过程中有着非常重要的地位,而且大部分肿瘤细胞中都存在Ras信号通路的上调,随着Ras信号通路的作用机制研究的逐渐透彻,这条通路上的Ras,Raf,MEK,ERK等重要激酶成为了研发治疗肿瘤药物的重要作用靶点。属于多因素疾病的肿瘤,单一靶点药物往往难以起到治疗的作用,对某一种酶或受体具有较强选择性和药效作用的单靶点药物,也不一定能够真正的达到治疗疾病的目的,而作用于多个靶点的药物其结构中含有作用于多个靶点的药效结构,可以产生多种药理活性,从而达到治疗肿瘤的目的[1]。
本课题以控制Ras/Raf/MEK/ERK信号通路中的关键信号蛋白—Ras蛋白活化所需的法尼基转移酶为中心,并选择与Ras关系密切同时在这个信号通路上起关键作用的Raf-1激酶为辅助靶点,利用计算机辅助药物设计的方法,采用药效团模型法,设计出同时作用于FTase和Raf-1激酶的多靶点作用药物,以期对肿瘤细胞产生较大的抑制作用,从而找到高活性、低毒性的用于特殊肿瘤的多靶点抗肿瘤药物。
本文利用catalyst软件构建了新型的Raf-1激酶抑制剂的药效团模型,结合课题组已构建的FTIs药效团模型,设计出了六个目标化合物,这些目标化合物对这两个靶点都具有很好的预测活性,且未见文献报道。采用合适的合成路线,合成出6个目标化合物,利用1H-NMR、13C-NMR、UV进行结构确认,用HPLC确定纯度。使用MTT的实验方法对目标化合物进行了体外药理活性的筛选,选取了与Ras/Raf/MEK/ERK信号通路密切相关的肝癌细胞HepG-2和胰腺癌细胞pcmc-1,测试目标化合物对这两种细胞的抑制活性。实验结果表明目标化合物对HepG-2和pcmc-1都具有较好的抑制活性,其中化合物B1的对HepG-2和pcmc-1的IC50值为48.46μmol/ml、15.43μmol/ml。将目标化合物的实测活性值与预测值活性值的进行比较,发现实测活性值与预测值活性值的变化趋势具有一致性,表明所构建的药效团模型具有一定的预测性和可靠性,对多靶点抗肿瘤药物的设计具有一定的指导意义。
本课题的创新之处:(1)针对不同靶点作用的多靶点抗肿瘤药物具有活性强、副作用小的优势,有可能最终成为有效的抗肿瘤药物,也是当前抗肿瘤药物的研究方向。本课题选取Ras/Raf/MEK/ERK信号通路上的FTase和Raf-1激酶作为靶点,利用计算机辅助药物设计技术,设计多靶点的抗肿瘤药物;(2)对目标化合物进行类药性分析,提高目标化合物的成药性;(3)目标化合物以氨甲苯酸为起始原料,合成过程简单,产率较高,得到6个未见报道的新型结构化合物;(4)提出利用计算机辅助药物设计技术设计多靶点作用药物的理念和方法,并进行了证实。
Ras/Raf/MEK/ERK signaling pathway exsits in all eukaryotic cells.This signaling pathway taked an important role in cell proliferation, differentiation, apoptosis, metastasis and metabolic and increases in most tumor cells.The important kinases Ras, Raf, MEK and ERK in this signaling pathway becomes the crucial targets for the investigation of anti-tumor agents. Tumor belongs to one of multifactorial diseases. Single targets agents that have a strong selectivity and efficacy on a particular enzyme or receptor usually have little effect on tumor therapy. It’s difficult for single targets to achieve the pursose of tumor therapy. In the case that they contain efficacy structures affecting on multiple targets, multi-targets agents may produce a variety of pharmacological activities so as to cure cancer.
The protein Ras is the crucial signaling protein in the Ras/Raf/MEK/ERK signaling transduction.This investigation chosed the Farnesyltransferase which can catslytic non-activated Ras-GDP to activated Ras-GTP as the main target and Raf-1 kinase which has a close relationship with Ras and plays an key role in this transduction simultaneously as the secondary target.Six multi-targets compounds which have an effect on FTase an Raf-1 kinases at the same time were designed by the use of computer aided drug design in the hope that they could have stronger inhibitory effect on tumor cells .The ultimate goal is to find the high activity and low toxicity multi-targets agents for specific cancer.
A new pharmacophore model of Raf-1 kinase inhibitors were constructed by the sofeware catalyst in the investigation. The six targets compounds matched with phar–macophore model of FTIs and Raf-1 kinase very well and had good predictive acti–vity(none was reported).The targets compounds were screened in vitro by the use of MTT. Hepatoma cells HepG-2 and pancreatic cancer cells pcmc-1 were chosed because of their close relationship with the Ras/Raf/MEK/ERK signaling transduction. The target compounds had a good inhibition effect on these two kinds of tumor cells. The IC50 of compound B1 affecting on HepG-2 and pcmc-1 were 48.46μmol/ml and 15.43μmol/ml respectively. Comparising the actual activity with the predicted activity, it was found that their mutative trends were consistent. This result indicated that the pharmacophore model of FTIs and Raf-1 kinase inhibitors has a certain predictability and reliability. The investigation has some guiding significance in some degree to the design of new anti-tumor agents.
The innovations of this investigation: (1) multi-targets anti-tumor agents which have effect on different targets take the advantages of strong activity and little side effects. The investigation designed multi-targets agents affecting on FTase and Raf-1 kinases by the use of CADD. (2) analysising the medicine of the guiding compounds increased their druggability. (3) the guiding compounds were easy to be synthesized and have not been reported in other literature. (4) the methods were proposed and confirmed that multi-targets anti-tumor agents can be designed by the use of CADD.
本课题以控制Ras/Raf/MEK/ERK信号通路中的关键信号蛋白—Ras蛋白活化所需的法尼基转移酶为中心,并选择与Ras关系密切同时在这个信号通路上起关键作用的Raf-1激酶为辅助靶点,利用计算机辅助药物设计的方法,采用药效团模型法,设计出同时作用于FTase和Raf-1激酶的多靶点作用药物,以期对肿瘤细胞产生较大的抑制作用,从而找到高活性、低毒性的用于特殊肿瘤的多靶点抗肿瘤药物。
本文利用catalyst软件构建了新型的Raf-1激酶抑制剂的药效团模型,结合课题组已构建的FTIs药效团模型,设计出了六个目标化合物,这些目标化合物对这两个靶点都具有很好的预测活性,且未见文献报道。采用合适的合成路线,合成出6个目标化合物,利用1H-NMR、13C-NMR、UV进行结构确认,用HPLC确定纯度。使用MTT的实验方法对目标化合物进行了体外药理活性的筛选,选取了与Ras/Raf/MEK/ERK信号通路密切相关的肝癌细胞HepG-2和胰腺癌细胞pcmc-1,测试目标化合物对这两种细胞的抑制活性。实验结果表明目标化合物对HepG-2和pcmc-1都具有较好的抑制活性,其中化合物B1的对HepG-2和pcmc-1的IC50值为48.46μmol/ml、15.43μmol/ml。将目标化合物的实测活性值与预测值活性值的进行比较,发现实测活性值与预测值活性值的变化趋势具有一致性,表明所构建的药效团模型具有一定的预测性和可靠性,对多靶点抗肿瘤药物的设计具有一定的指导意义。
本课题的创新之处:(1)针对不同靶点作用的多靶点抗肿瘤药物具有活性强、副作用小的优势,有可能最终成为有效的抗肿瘤药物,也是当前抗肿瘤药物的研究方向。本课题选取Ras/Raf/MEK/ERK信号通路上的FTase和Raf-1激酶作为靶点,利用计算机辅助药物设计技术,设计多靶点的抗肿瘤药物;(2)对目标化合物进行类药性分析,提高目标化合物的成药性;(3)目标化合物以氨甲苯酸为起始原料,合成过程简单,产率较高,得到6个未见报道的新型结构化合物;(4)提出利用计算机辅助药物设计技术设计多靶点作用药物的理念和方法,并进行了证实。
Ras/Raf/MEK/ERK signaling pathway exsits in all eukaryotic cells.This signaling pathway taked an important role in cell proliferation, differentiation, apoptosis, metastasis and metabolic and increases in most tumor cells.The important kinases Ras, Raf, MEK and ERK in this signaling pathway becomes the crucial targets for the investigation of anti-tumor agents. Tumor belongs to one of multifactorial diseases. Single targets agents that have a strong selectivity and efficacy on a particular enzyme or receptor usually have little effect on tumor therapy. It’s difficult for single targets to achieve the pursose of tumor therapy. In the case that they contain efficacy structures affecting on multiple targets, multi-targets agents may produce a variety of pharmacological activities so as to cure cancer.
The protein Ras is the crucial signaling protein in the Ras/Raf/MEK/ERK signaling transduction.This investigation chosed the Farnesyltransferase which can catslytic non-activated Ras-GDP to activated Ras-GTP as the main target and Raf-1 kinase which has a close relationship with Ras and plays an key role in this transduction simultaneously as the secondary target.Six multi-targets compounds which have an effect on FTase an Raf-1 kinases at the same time were designed by the use of computer aided drug design in the hope that they could have stronger inhibitory effect on tumor cells .The ultimate goal is to find the high activity and low toxicity multi-targets agents for specific cancer.
A new pharmacophore model of Raf-1 kinase inhibitors were constructed by the sofeware catalyst in the investigation. The six targets compounds matched with phar–macophore model of FTIs and Raf-1 kinase very well and had good predictive acti–vity(none was reported).The targets compounds were screened in vitro by the use of MTT. Hepatoma cells HepG-2 and pancreatic cancer cells pcmc-1 were chosed because of their close relationship with the Ras/Raf/MEK/ERK signaling transduction. The target compounds had a good inhibition effect on these two kinds of tumor cells. The IC50 of compound B1 affecting on HepG-2 and pcmc-1 were 48.46μmol/ml and 15.43μmol/ml respectively. Comparising the actual activity with the predicted activity, it was found that their mutative trends were consistent. This result indicated that the pharmacophore model of FTIs and Raf-1 kinase inhibitors has a certain predictability and reliability. The investigation has some guiding significance in some degree to the design of new anti-tumor agents.
The innovations of this investigation: (1) multi-targets anti-tumor agents which have effect on different targets take the advantages of strong activity and little side effects. The investigation designed multi-targets agents affecting on FTase and Raf-1 kinases by the use of CADD. (2) analysising the medicine of the guiding compounds increased their druggability. (3) the guiding compounds were easy to be synthesized and have not been reported in other literature. (4) the methods were proposed and confirmed that multi-targets anti-tumor agents can be designed by the use of CADD.
引文
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[1]Wilhelm S M, Carter C, Tang L, et al. BAY-43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis[J] Cancer Res, 2004, 64(19): 7099-109.
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[1]Wilhelm S M, Carter C, Tang L, et al. BAY-43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis[J] Cancer Res, 2004, 64(19): 7099-109.
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[21] J.M.Kurie, H.C.MorseⅢ, M.A.Principato, J.S.Wax, J, et al: v-myc and v-raf act synergistically to induce B-cell tumors in pristine-primed adult BALBC mice, Oncogene, 1990, 5: 577-582.
[22] L.K.Rushworth, A.D.Hindley, E.O.Neill, W.Kolch: Regulation and role of Raf-1/B-Raf heterodimerization, Mol. Cell. Biol. 2006, 26: 2262-2272.
[23] Wilhelm SM, Carter C, Tang L etal: BAY43-9006exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis, Cancer Res, 2004, 64: 7099-7109.
[24] Nagar B, Bormmann W, Pellicena P et al: Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571), Cancer Res, 2002, 62: 1938-1942.
[25] Carlos Garcia Echeverria: Protein and lipid kinase inhibitors as targeted anti cancer agents of the Ras/Raf/MEK/ERK and PI3K/PKB pathways, Purinergic Signaling, 2009, 5: 117-125.
[26] Amiri P, Aikawa ME, Dove J, et al: CHIR-265 is a potent selective inhibitor of c-Raf/B-Raf/mutB-Raf that effectively inhibits roliferation and survival of cancer cell lines with Ras/Raf pathway mutations (abstract4855), Proc Am Assoc Cancer Res 47.
[27]Joshua T.Dilworth, Janice M.Kraniak, et: molecular targets for emerging antitum or therapies for neurofibromatosis type1, Biochemical phamarmacology, 2006, 17: 1485-1492.
[28]Timothy B.Lowinger, Brnd Ried et al: design and discovery of small molecules targeting Raf-1 kinase. Current Pharmaceutical Design, 2002, 8: 2269-2278.
[29]Roger A.Smith, James Barbosa et al: Discovery of heterocyclic ureas as a new class ofRaf kinase inhibitors: identification of a second generation lead by a combinatorial chemistry approach. Bioorganic & Chemistry Letters, 2001, 11: 2775-2778.
[30]Eun Young Song, Navneet Kaur, et al: synthesis of amide and urea derivatives of benzothiazole as Raf-1 inhibitors, European Journal of Medicinal Chemistry 2008, 14: 1519-1524.
[31]Octerloney McDonald, Karen Lackey, et al: Azastilbenes as potent and selective c-Raf inhibitors, Bioorganic & Medicinal Chemistry Letters, 2006, 16: 5378- 5383.
[32] Wood. E. G. Kuyper, L. Petrov, K.G. Hunter, R.N. et a1: Discovery and In Vitro Evaluation of Potent TrkA Kinase Inhibitors: Oxindole and Azaoxindoles Bioorg [J] Med Chem Lett, 2004, 14: 953-957.
[33]. F. George Njoroge, Bancha Vibulbhan, Bridgehead modification of trihalocy clohepta benzopyridine lead to a potent farnesyl protein transferase inhibitor with improve dora -l metabolic stability. Bioorganic & Medicinal Chemistry Letters, 2004, 14: 5899– 5902.
[34]. Gary T. Wang,Xilu Wang, Weibo Wang, Design and synthesis of o-trifluoro methylbi -phenyl substituted2-amino-nicotinonitriles as inhibitors of farnesyltransferase. Bioor -ganic & Medicinal Chemistry Letters, 2005, 15: 153–158.
[35]. (a) van Cutsem, E.; van de Velde, H.; Karasek, P.; Clin. Oncol. 2004, 22: 1430–1438; (b) Venet, M.; End, D.; Angibaud, P. Curr. Top. Med. Chem. 2003, 3: 1095–1102; (c) Caponigro, F. Casale, M. Bryce, J. Expert Opin. Invest. Drugs, 2003, 12: 943–954; (d) Norman, P. Curr. Opin. Invest. Drugs , 2002, 3.
[36]. Relevant studies using tipifarnib as a template: (a) Angibaud, P.; Bourdrez, X.; End, D. W.; Freyne, E.; Janicot, M.; Lezouret, P.; Ligny, Y.; Mannens, G.; Chem. Abstr. 1999, 132: 35705.
[37]. Qun Li,* Tongmei Li, Keith W. Woods: Benzimidazolones and indoles as non-thiol -farnesyltransferase inhibitors based on tipifarnib scaffold: synthesis and activity, Bioo -rganic & Medicinal Chemistry Letters, 2005, 15: 2918–2922.
[38]. Patrick Angibaud, Xavier Bourdrez, David W: Substituted azoloquinolines and quina -zolines as new potent farnesyl protein transferase inhibitors. Bioorganic & Medicinal Chemistry Letters, 2003, 13: 4365–4369.
[39]陆嘉德,郭哗,肿瘤靶向治疗新探:多靶点Raf激酶抑制剂,《中国癌症杂志》,2007,1: 17
[40]李彪,李晓玫,Raf-1蛋白激酶的研究新进展,基础医学,1999,1: 18.
[41]姜凤超,多靶点作用药物及其设计,药学学报, 2009, 44(3):282-287.