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Bcl-2 、 Bcl-xL 抑制剂与抗癌

Bcl-2 、 Bcl-xL 抑制剂与抗癌. 孙鲁超 5091719014. 细胞凋亡信号转导途径. 1. Fas/ CD95 信号转导途径. 2. TNFR_1 信号转导途径. 3. TRAIL 介导的凋亡信号通路. 4. MAPK、JAK_STAT 信号转导途径. 5. G 蛋白信号转导途径. J Environ Occup Med , Feb 2004 Vol. 21 No. 1. Fas/ CD95 信号转导途径.

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Bcl-2 、 Bcl-xL 抑制剂与抗癌

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  1. Bcl-2、Bcl-xL抑制剂与抗癌 孙鲁超 5091719014

  2. 细胞凋亡信号转导途径 1 Fas/ CD95 信号转导途径 2 TNFR_1 信号转导途径 3 TRAIL 介导的凋亡信号通路 4 MAPK、JAK_STAT 信号转导途径 5 G蛋白信号转导途径 J Environ Occup Med, Feb 2004 Vol. 21 No. 1

  3. Fas/ CD95 信号转导途径 • Fas/ CD95 是典型的死亡受体, 属于I型膜蛋白。在胞质内有一段约80 个氨基酸组成的肽链, 称为“死亡结构域”( death domain, DD) 。Fas 的配体( FasL) 以同源三聚体形式存在，该三聚体为一种叫Fas 相关死亡蛋白( Fas associated death domain protein,FADD) 提供了高亲和力位点。FADD 是一种胞质内蛋白, 包含一个N 末端的死亡效应域( death effect domain, DED) 和一个C 末端的DD。

  4. Fas/ CD95 信号转导途径

  5. TNFR_1 信号转导途径 TNFR_1 信号转导的途径与Fas 信号转导途径相似

  6. Bcl-2家族 • Bcl-2亚家族可以抑制线粒体释放细胞色素C, 从而影响APAF-1与Caspase-9-前体的结合及Caspase-9的活化, 抑制细胞凋亡。BH3 亚家族的成员可以通过与Bcl-2 亚家族的同源区, 竞争结合Bcl-2, 从而使APAF-1 与Caspase-9前体结合, 启动凋亡。 • Bcl-2家族的成员通常以二聚体的形式发挥作用,Bcl-2/Bcl-2,Bcl-2/Bax和Bcl-2/Bcl-xL抑制细胞凋亡

  7. HA14-1 • Ethyl [2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)]-4H-chromene-3-carboxylate Tetrahedron Letters Volume 49, Issue 20, 12 May 2008, Pages 3276-3278

  8. To the best of our knowledge, only analogues modified on the aromatic ring have been reported. The biological tests have shown that the bromine in position 6 could be replaced by some alkyl or aryl groups

  9. (i) ethylcyanoacetate, EtOH, 3A Mol. Sieves, rt, overnight

  10. Reagents and conditions: (i) ethylvinylether (6.3 equiv), camphorsulfonic acid (0.2 equiv), THF, 10 C, 4 h then Et3N and K2CO3 (90%); (ii) ethylcyanoacetate (1.1 equiv), EtOH, 3A ˚ mol. Sieves, rt, overnight (65%); (iii) Amberlyst 15, 4A ˚ mol. Sieves, CH2Cl2, rt, 5 h (80%); (iv) general procedure: malonate or cyanoacetamide (1.1 equiv), EtOH, 4 A˚ mol. Sieves, piperidine (cat), rt, 5 h, 5a (70%), 5b (79%), 5c (81%), 5d (73%).

  11. HA14-1类似物SV30 • However, HA14-1 is a relatively unstable molecule, which further, is a mixture of two stereoisomers. • One of our groups has recently prepared SV30, a new analogue of HA14-1 which is a single stereoisomer, and furthermore appears more stable than HA14-1. Journal of Controlled Release 151 (2011) 74–82

  12. ABT-263和ABT-737

  13. (*) Patients with small-cell carcinoma. (†) Patients with pulmonary carcinoid tumors Journal of Clinical Oncology 2011;29(7):909-16

  14. Summary of changes made to ABT-737 ( 32 ) resulting in ABT-263 Expert Opinion on Drug Discovery, Volume 3, Number 9, September 2008 , pp. 1123-1143(21)

  15. NMR-derived structure of diphenylmethane compound 1 bound to Bcl-2 Bioorganic & Medicinal Chemistry Letters 20 (2010) 6587–6591

  16. NMR-derived structure of Bcl-2 in complex with compound 27

  17. 针对细胞凋亡途径的调控蛋白设计新的靶点

  18. 成骨细胞凋亡受体内激素和生长因子等因素调节,Xian 等研究发现IGF- 1能对多种因素引起的细胞凋亡有抑制作用, 保护成骨细胞免于有害物质的毒性作用, 使成骨细胞增加。 • Bcl- 2 家族在调节成骨细胞凋亡中起重要作用。……Bcl- 2 和Bax在软骨和成骨细胞中的表达, 维持骨基质合成和降解的平衡, 调节着骨形成和骨吸收的平衡。 CHINESE JOURNAL OF INT EGRAT IVE MEDICINE ON CARDIO- / CEREBROVASCU LAR DISEASEJune 2008Vo1. 6No. 6

  19. 珍珠菜提取物ZE4可通过上调Fas/Fas L 基因, 上调TRA IL 及DR5表达, 下调Bcl- 2表达, 上调Caspase 3表达等途径诱导SMMC-7721肿瘤细胞发生凋亡, 具有良好的抗肿瘤效果。 上海中医药杂志 2010年 第44卷 第3期

  20. 姜黄素可通过抑制Bcl表达增加Bax的表达进一步激活半胱氨酸天冬氨酸蛋白酶8、半胱氨酸天冬氨酸蛋白酶3，抑制肺腺癌A549细胞生长，提高对肿瘤坏死因子相关凋亡诱导配体敏感性。姜黄素可通过抑制Bcl表达增加Bax的表达进一步激活半胱氨酸天冬氨酸蛋白酶8、半胱氨酸天冬氨酸蛋白酶3，抑制肺腺癌A549细胞生长，提高对肿瘤坏死因子相关凋亡诱导配体敏感性。 中国临床康复 第10卷 第31期

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  22. Thank you

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