合成并评价取代的六氢萘作为新型 Mcl-1/BimBH3 相互作用抑制剂。
Synthesis and evaluation of substituted hexahydronaphthalenes as novel inhibitors of the Mcl-1/BimBH3 interaction.
机构信息
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
出版信息
Bioorg Med Chem Lett. 2012 Sep 15;22(18):5961-5. doi: 10.1016/j.bmcl.2012.07.050. Epub 2012 Jul 24.
Abstract
Mcl-1, an anti-apoptotic member of the Bcl-2 protein family, is overexpressed in a broad range of human cancers and plays a critical role in conferring resistance to chemotherapy. In the course of screening a natural product-like library of sesquiterpenoid analogs, we identified substituted hexahydronaphthalenes that showed activity against the Mcl-1/BimBH3 interaction in vitro. Here, we describe the synthesis of a small library of analogs and their biological evaluation. The most potent inhibitor in the series (19) exhibits an IC(50) of 8.3 μM by ELISA and disrupts the interaction between endogenously expressed Mcl-1 and Bim in cultured MDA-MB-468 breast cancer cells.
摘要
Mcl-1 是 Bcl-2 蛋白家族的一种抗凋亡成员，在广泛的人类癌症中过表达，并且在赋予对化疗的抗性方面发挥着关键作用。在筛选天然产物样倍半萜类似物文库的过程中，我们鉴定出了具有体外抗 Mcl-1/BimBH3 相互作用活性的取代六氢萘。在这里，我们描述了一个小型类似物文库的合成及其生物学评价。该系列中最有效的抑制剂（19）通过 ELISA 显示出 8.3 μM 的 IC50，并破坏了在培养的 MDA-MB-468 乳腺癌细胞中内源性表达的 Mcl-1 和 Bim 之间的相互作用。
相似文献
1
Synthesis and evaluation of substituted hexahydronaphthalenes as novel inhibitors of the Mcl-1/BimBH3 interaction.合成并评价取代的六氢萘作为新型 Mcl-1/BimBH3 相互作用抑制剂。
Bioorg Med Chem Lett. 2012 Sep 15;22(18):5961-5. doi: 10.1016/j.bmcl.2012.07.050. Epub 2012 Jul 24.
2
High-throughput screen for the chemical inhibitors of antiapoptotic bcl-2 family proteins by multiplex flow cytometry.通过多重流式细胞术对抗凋亡bcl-2家族蛋白的化学抑制剂进行高通量筛选。
Assay Drug Dev Technol. 2011 Oct;9(5):465-74. doi: 10.1089/adt.2010.0363. Epub 2011 May 11.
3
Akt-dependent glucose metabolism promotes Mcl-1 synthesis to maintain cell survival and resistance to Bcl-2 inhibition.Akt 依赖性葡萄糖代谢促进 Mcl-1 的合成，以维持细胞存活并抵抗 Bcl-2 抑制。
Cancer Res. 2011 Aug 1;71(15):5204-13. doi: 10.1158/0008-5472.CAN-10-4531. Epub 2011 Jun 13.
4
Emerging role of Mcl-1 in actively counteracting BH3-only proteins in apoptosis.Mcl-1在凋亡过程中积极对抗仅含BH3结构域蛋白方面的新作用。
Cell Death Differ. 2006 Aug;13(8):1263-7. doi: 10.1038/sj.cdd.4401952. Epub 2006 May 5.
5
EGFR signaling defines Mcl⁻1 survival dependency in neuroblastoma.表皮生长因子受体（EGFR）信号传导决定了神经母细胞瘤中髓细胞白血病序列1（Mcl⁻1）对细胞存活的依赖性。
Cancer Biol Ther. 2015;16(2):276-86. doi: 10.1080/15384047.2014.1002333.
6
Cafestol overcomes ABT-737 resistance in Mcl-1-overexpressed renal carcinoma Caki cells through downregulation of Mcl-1 expression and upregulation of Bim expression.咖啡醇通过下调Mcl-1表达和上调Bim表达克服Mcl-1过表达的肾癌Caki细胞中的ABT-737耐药性。
Cell Death Dis. 2014 Nov 6;5(11):e1514. doi: 10.1038/cddis.2014.472.
7
Marinopyrrole derivatives with sulfide spacers as selective disruptors of Mcl-1 binding to pro-apoptotic protein Bim.具有硫化物间隔基的海杆菌吡咯衍生物作为Mcl-1与促凋亡蛋白Bim结合的选择性破坏剂。
Mar Drugs. 2014 Jul 29;12(8):4311-25. doi: 10.3390/md12084311.
8
c-Myc dependent expression of pro-apoptotic Bim renders HER2-overexpressing breast cancer cells dependent on anti-apoptotic Mcl-1.c-Myc 依赖性表达促凋亡 Bim 使 HER2 过表达的乳腺癌细胞依赖抗凋亡 Mcl-1。
Mol Cancer. 2011 Sep 7;10:110. doi: 10.1186/1476-4598-10-110.
9
The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms.HSP90 抑制剂 XL888 通过多种机制克服了 BRAF 抑制剂耐药。
Clin Cancer Res. 2012 May 1;18(9):2502-14. doi: 10.1158/1078-0432.CCR-11-2612. Epub 2012 Feb 20.
10
The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner.BH3 ɑ 螺旋模拟物 BH3-M6 可破坏 Bax、Bak、Bad 或 Bim 与 Bcl-X(L)、Bcl-2 和 MCL-1 蛋白-蛋白相互作用，并以 Bax 和 Bim 依赖的方式诱导细胞凋亡。
J Biol Chem. 2011 Mar 18;286(11):9382-92. doi: 10.1074/jbc.M110.203638. Epub 2010 Dec 9.
引用本文的文献
1
Synthesis and structure-activity relationship of coumarins as potent Mcl-1 inhibitors for cancer treatment.香豆素类作为有效的 Mcl-1 抑制剂的合成及构效关系研究及其在癌症治疗中的应用。
Bioorg Med Chem. 2021 Jan 1;29:115851. doi: 10.1016/j.bmc.2020.115851. Epub 2020 Nov 7.
2
New dimension in therapeutic targeting of BCL-2 family proteins.BCL-2家族蛋白治疗靶点的新维度。
Oncotarget. 2015 May 30;6(15):12862-71. doi: 10.18632/oncotarget.3868.
3
Designed BH3 peptides with high affinity and specificity for targeting Mcl-1 in cells.设计具有高亲和力和特异性的BH3肽，用于在细胞中靶向Mcl-1。
ACS Chem Biol. 2014 Sep 19;9(9):1962-8. doi: 10.1021/cb500340w. Epub 2014 Jul 23.
4
Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design.利用片段基方法和基于结构的设计发现有效的髓样细胞白血病 1（Mcl-1）抑制剂。
J Med Chem. 2013 Jan 10;56(1):15-30. doi: 10.1021/jm301448p. Epub 2012 Dec 17.
本文引用的文献
1
Discovery of marinopyrrole A (maritoclax) as a selective Mcl-1 antagonist that overcomes ABT-737 resistance by binding to and targeting Mcl-1 for proteasomal degradation.发现了 marinopyrrole A（maritoclax），它是一种选择性的 Mcl-1 拮抗剂，通过与 Mcl-1 结合并将其靶向蛋白酶体降解来克服 ABT-737 的耐药性。
J Biol Chem. 2012 Mar 23;287(13):10224-10235. doi: 10.1074/jbc.M111.334532. Epub 2012 Feb 6.
2
The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy.Bcl-2 及其生存相关蛋白在肿瘤发生和癌症治疗中的作用。
Cell Death Differ. 2011 Sep;18(9):1414-24. doi: 10.1038/cdd.2011.17. Epub 2011 Mar 18.
3
The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner.BH3 ɑ 螺旋模拟物 BH3-M6 可破坏 Bax、Bak、Bad 或 Bim 与 Bcl-X(L)、Bcl-2 和 MCL-1 蛋白-蛋白相互作用，并以 Bax 和 Bim 依赖的方式诱导细胞凋亡。
J Biol Chem. 2011 Mar 18;286(11):9382-92. doi: 10.1074/jbc.M110.203638. Epub 2010 Dec 9.
4
The BCL-2 protein family: opposing activities that mediate cell death.BCL-2蛋白家族：介导细胞死亡的相反活性
Nat Rev Mol Cell Biol. 2008 Jan;9(1):47-59. doi: 10.1038/nrm2308.
5
Bim and the pro-survival Bcl-2 proteins: opposites attract, ERK repels.Bim与促生存的Bcl-2蛋白：异性相吸，ERK相斥。
Cell Cycle. 2007 Sep 15;6(18):2236-40. doi: 10.4161/cc.6.18.4728. Epub 2007 Jul 10.
6
Structural insights into the degradation of Mcl-1 induced by BH3 domains.BH3结构域诱导的Mcl-1降解的结构解析
Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6217-22. doi: 10.1073/pnas.0701297104. Epub 2007 Mar 27.
7
Pyrogallol-based molecules as potent inhibitors of the antiapoptotic Bcl-2 proteins.基于连苯三酚的分子作为抗凋亡Bcl-2蛋白的有效抑制剂。
J Med Chem. 2007 Apr 19;50(8):1723-6. doi: 10.1021/jm061400l. Epub 2007 Mar 23.
8
The Bcl-2 apoptotic switch in cancer development and therapy.癌症发展与治疗中的Bcl-2凋亡开关
Oncogene. 2007 Feb 26;26(9):1324-37. doi: 10.1038/sj.onc.1210220.
9
Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia.急性髓系白血病中细胞凋亡敏感性及对BH3模拟物ABT-737耐药的机制
Cancer Cell. 2006 Nov;10(5):375-88. doi: 10.1016/j.ccr.2006.10.006.
10
At the gates of death.在死亡之门。
Cancer Cell. 2006 May;9(5):328-30. doi: 10.1016/j.ccr.2006.05.004.
Zotero 插件