药学学报, 2021, 56(5): 1238-1245
引用本文:
付正豪, 闫干干, 戚海燕, 刘晓平, 陈云雨*. 靶向β-catenin/TCF4相互作用抑制剂在肿瘤分子治疗中的研究进展[J]. 药学学报, 2021, 56(5): 1238-1245.
FU Zheng-hao, YAN Gan-gan, QI Hai-yan, LIU Xiao-ping, CHEN Yun-yu*. Recent advances in novel anticancer agents targeting β-catenin/TCF4 interaction for molecular cancer therapeutics[J]. Acta Pharmaceutica Sinica, 2021, 56(5): 1238-1245.

靶向β-catenin/TCF4相互作用抑制剂在肿瘤分子治疗中的研究进展
付正豪, 闫干干, 戚海燕, 刘晓平, 陈云雨*
皖南医学院药物筛选与评价研究所, 安徽 芜湖 241002
摘要:
经典Wnt信号通路的异常活化与恶性肿瘤的发生与发展密切相关,β-catenin/TCF4(T-cell factor 4)相互作用作为Wnt信号通路中的“分子开关”,促进了肿瘤的转移与复发,被认为是广谱高选择性抗肿瘤药物开发的理想靶标之一。目前,PKF222-815、iCRT3/5/14、LF3和血根碱等靶向β-catenin/TCF4相互作用的抑制剂已在结直肠癌和肝癌等肿瘤的实验治疗中展现出良好的应用前景。本文将对β-catenin分子结构、生物学功能及β-catenin/TCF4相互作用抑制剂的研究进展进行综述和展望,以期为新型高选择性Wnt抑制剂的筛选与发现提供有益的借鉴和参考。
关键词:    Wnt抑制剂      β-catenin/TCF4相互作用      β-catenin/LEF1相互作用      蛋白质-蛋白质相互作用      抗肿瘤作用     
Recent advances in novel anticancer agents targeting β-catenin/TCF4 interaction for molecular cancer therapeutics
FU Zheng-hao, YAN Gan-gan, QI Hai-yan, LIU Xiao-ping, CHEN Yun-yu*
Institute for Drug Screening and Evaluation, Wannan Medical College, Wuhu 241002, China
Abstract:
Wnt/β-catenin signaling pathway plays an important role in the proliferation, growth, invasion, and metastasis of human cancers. Moreover, β-catenin/T-cell factor 4 (TCF4) interaction regulates the transcription of the key oncogenes in Wnt/β-catenin signaling pathway. Therefore, β-catenin/TCF4 interaction would be a promising therapeutic target for the development of highly selective anticancer agents. At present, most ongoing small-molecule inhibitors targeting β-catenin/TCF4 interaction, including PKF222-815, iCRT3/5/14, LF3, and sanguinarine, have been developed in preclinical studies for human cancer therapeutics. In this review, we summarized the research advances of up-to date inhibitors targeting β-catenin/TCF4 interaction, including the molecular structure and cellular functions of β-catenin in canonical Wnt signaling pathway. This review holds a hopeful avenue for the development of novel and highly selective Wnt inhibitors targeting β-catenin/TCF4 interaction for future anticancer strategy.
Key words:    Wnt inhibitor    β-catenin/TCF4 interaction    β-catenin/LEF1 interaction    protein-protein interaction    anticancer activity   
收稿日期: 2021-01-05
DOI: 10.16438/j.0513-4870.2021-0018
基金项目: 国家自然科学基金资助项目(81703546);安徽省自然科学基金资助项目(1808085QH265);安徽省高校自然科学研究重大项目(KJ2019ZD30).
通讯作者: 陈云雨,Tel:86-553-3932414,E-mail:chenyunyu1984@163.com
Email: chenyunyu1984@163.com
相关功能
PDF(950KB) Free
打印本文
0
作者相关文章
付正豪  在本刊中的所有文章
闫干干  在本刊中的所有文章
戚海燕  在本刊中的所有文章
刘晓平  在本刊中的所有文章
陈云雨*  在本刊中的所有文章

参考文献:
[1] Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68:394-424.
[2] Coleman MP. Cancer survival:global surveillance will stimulate health policy and improve equity[J]. Lancet, 2014, 383:564-573.
[3] Zhong Z, Virshup DM. Wnt signaling and drug resistance in cancer[J]. Mol Pharmacol, 2020, 97:72-89.
[4] Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities[J]. Cell, 2017, 169:985-999.
[5] Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer[J]. Oncogene, 2017, 36:1461-1473.
[6] Cheng X, Xu X, Chen D, et al. Therapeutic potential of targeting the Wnt/β-catenin signaling pathway in colorectal cancer[J]. Biomed Pharmacother, 2019, 110:473-481.
[7] Cui C, Zhou X, Zhang W, et al. Is β-catenin a druggable target for cancer therapy?[J] Trends Biochem Sci, 2018, 43:623-634.
[8] Jamieson C, Sharma M, Henderson BR. Targeting the β-catenin nuclear transport pathway in cancer[J]. Semin Cancer Biol, 2014, 27:20-29.
[9] Shang S, Hua F, Hu Z. The regulation of β-catenin activity and function in cancer:therapeutic opportunities[J]. Oncotarget, 2017, 8:33972-33989.
[10] Mis M, O'Brien S, Steinhart Z, et al. IPO11 mediates β-catenin nuclear import in a subset of colorectal cancers[J]. J Cell Biol, 2020, 219:e201903017.
[11] Xu X, Sun PL, Li JZ, et al. Aberrant Wnt1/β-catenin expression is an independent poor prognostic marker of non-small cell lung cancer after surgery[J]. J Thorac Oncol, 2011, 6:716-724.
[12] Yang J, Chen J, He J, et al. Wnt signaling as potential therapeutic target in lung cancer[J]. Expert Opin Ther Targets, 2016, 20:999-1015.
[13] Rice SJ, Liu X, Hyland V, et al. Mutations in genes connected with the TCF7L2 transcription factor are associated with a poor prognosis in non-small cell lung cancer[J]. Lung Cancer, 2020, 141:97-100.
[14] Hovanes K, Li TW, Munguia JE, et al. Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer[J]. Nat Genet, 2001, 28:53-57.
[15] Bleckmann A, Siam L, Klemm F, et al. Nuclear LEF-1/TCF-4 correlate with poor prognosis but not with nuclear β-catenin in cerebral metastasis of lung adenocarcinomas[J]. Clin Exp Metastasis, 2013, 30:471-482.
[16] Nguyen DX, Chiang AC, Zhang XH, et al. WNT/TCF signaling through LEF-1 and HOXB9 mediates lung adenocarcinoma metastasis[J]. Cell, 2009, 138:51-62.
[17] Chen CY, Jan YH, Juan YH, et al. Fucosyltransferase 8 as a functional regulator of non-small cell lung cancer[J]. Proc Natl Acad Sci U S A, 2013, 110:630-635.
[18] Iqbal W, Alkarim S, AlHejin A, et al. Targeting signal transduction pathways of cancer stem cells for therapeutic opportunities of metastasis[J]. Oncotarget, 2016, 7:76337-76353.
[19] Ghosh N, Hossain U, Mandal A, et al. The Wnt signaling pathway:a potential therapeutic target against cancer[J]. Ann N Y Acad Sci, 2019, 1443:54-74.
[20] Stewart DJ. Wnt signaling pathway in non-small cell lung cancer[J]. J Natl Cancer Inst, 2014, 106:djt356.
[21] Jin J, Zhan P, Katoh M, et al. Prognostic significance of β-catenin expression in patients with non-small cell lung cancer:a meta-analysis[J]. Transl Lung Cancer Res, 2017, 6:97-108.
[22] Lepourcelet M, Chen YN, France DS, et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex[J]. Cancer Cell, 2004, 5:91-102.
[23] Wei W, Chua MS, Grepper S, et al. Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo[J]. Int J Cancer, 2010, 126:2426-2436.
[24] Gandhirajan RK, Staib PA, Minke K, et al. Small molecule inhibitors of Wnt/beta-catenin/lef-1 signaling induces apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo[J]. Neoplasia, 2010, 12:326-335.
[25] Gonsalves FC, Klein K, Carson BB, et al. An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway[J]. Proc Natl Acad Sci U S A, 2011, 108:5954-5963.
[26] Hsieh TH, Hsu CY, Tsai CF, et al. A novel cell penetrating peptide suppresses breast tumorigenesis by inhibiting β-catenin/LEF-1 signaling[J]. Sci Rep, 2016, 6:19156.
[27] Fang L, Zhu Q, Neuenschwander M, et al. A small-molecule antagonist of the β-catenin/TCF4 interaction blocks the self-renewal of cancer stem cells and suppresses tumorigenesis[J]. Cancer Res, 2016, 76:891-901.
[28] Hua F, Shang S, Yang YW, et al. TRIB3 interacts with β-catenin and TCF4 to increase stem cell features of colorectal cancer stem cells and tumorigenesis[J]. Gastroenterology, 2019, 156:708-721.
[29] Achkar IW, Mraiche F, Mohammad RM, et al. Anticancer potential of sanguinarine for various human malignancies[J]. Future Med Chem, 2017, 9:933-950.
[30] Almeida IV, Fernandes LM, Biazi BI, et al. Evaluation of the anticancer activities of the plant alkaloids sanguinarine and chelerythrine in human breast adenocarcinoma cells[J]. Anticancer Agents Med Chem, 2017, 17:1586-1592.
[31] Fu C, Guan G, Wang H. The anticancer effect of sanguinarine:a review[J]. Curr Pharm Des, 2018, 24:2760-2764.
[32] Yang J, Fang Z, Wu J, et al. Construction and application of a lung cancer stem cell model:antitumor drug screening and molecular mechanism of the inhibitory effects of sanguinarine[J]. Tumor Biol, 2016, 37:13871-13883.
[33] Zhu M, Gong Z, Wu Q, et al. Sanguinarine suppresses migration and metastasis in colorectal carcinoma associated with the inversion of EMT through the Wnt/β-catenin signaling[J]. Clin Transl Med, 2020, 10:1-12.
[34] Chen YY, Hu K, Fu ZH, et al. Development of a fluorescence polarization-based high-throughput screening assay to identify antagonists targeting β-catenin/TCF4 interaction[J]. Acta Pharm Sin (药学学报), 2020, 55:884-891.
[35] Chen Y, Fu Z, Li D, et al. Optimizations of a novel fluorescence polarization-based high-throughput screening assay for β-catenin/LEF1 interaction inhibitors[J]. Anal Biochem, 2021, 612:113966.
[36] Niu XY, Han MC, Li M, et al. Optimization of prokaryotic expression conditions and biological activity identification of recombinant human β-catenin[J]. J Microbiol (微生物学杂志), 2020, 40:58-66.
[37] Glahn-Martínez B, Benito-Peña E, Salis F, et al. Sensitive rapid fluorescence polarization immunoassay for free mycophenolic acid determination in human serum and plasma[J]. Anal Chem, 2018, 90:5459-5465.
[38] Behrens J, von Kries JP, Kühl M, et al. Functional interaction of beta-catenin with the transcription factor LEF-1[J]. Nature, 1996, 382:638-642.
[39] Huber O, Korn R, McLaughlin J, et al. Nuclear localization of beta-catenin by interaction with transcription factor LEF-1[J]. Mech Dev, 1996, 59:3-10.
[40] Morgan RG, Ridsdale J, Payne M, et al. LEF-1 drives aberrant β-catenin nuclear localization in myeloid leukemia cells[J]. Haematologica, 2019, 104:1365-1377.
[41] Araste F, Abnous K, Hashemi M, et al. Peptide-based targeted therapeutics:focus on cancer treatment[J]. J Control Release, 2018, 292:141-162.
[42] Erak M, Bellmann-Sickert K, Els-Heindl S, et al. Peptide chemistry toolbox-transforming natural peptides into peptide therapeutics[J]. Bioorg Med Chem, 2018, 26:2759-2765.
[43] He JY, Liang J, Xuan MS, et al. Effective strategies for improving the stability of peptides in vivo[J]. Acta Pharm Sin (药学学报), 2020, 55:25-32.
相关文献:
1.陈云雨, 胡克, 付正豪, 牛夏忆, 张晶, 刘晓平.靶向β-catenin/TCF4相互作用小分子抑制剂荧光偏振高通量筛选模型的建立与应用[J]. 药学学报, 2020,55(5): 884-891