We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×

Small-molecule inhibitors of Wnt signaling pathway: towards novel anticancer therapeutics

    Shilong Zheng

    RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA

    Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA

    ,
    Jiawang Liu

    RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA

    Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA

    ,
    Yanyuan Wu

    Division of Cancer Research & Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA

    Department of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA

    ,
    Tien L Huang

    RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA

    School of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USA

    &
    Guangdi Wang

    *Author for correspondence:

    E-mail Address: gwang@xula.edu

    RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA

    Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA

    Published Online:https://doi.org/10.4155/fmc.15.159

    Background: The Wnt signaling pathway involves secreted glycoproteins that bind to the Frizzled family receptors to activate intracellular signal transduction events that regulate cell proliferation, apoptosis, cell migration and many critical aspects of developmental biology. Discussion: Aberrant Wnt signaling underlies a wide range of pathologies in humans including tumor initiation, tumor growth, cell senescence, cell death, differentiation and metastasis. The inhibition of Wnt signaling offers a novel approach for anticancer therapeutics. Conclusion: Focusing on recent developments, we reviewed the small-molecule inhibitors targeting various components of Wnt signaling pathways and the progress from the discovery of lead compounds to highly potent inhibitors with significant therapeutic potential.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Nusse R, Varmus HE. Wnt genes. Cell 69(7), 1073–1087 (1992).
    • 2 Stewart DJ. Wnt signaling pathway in non–small cell lung cancer. J. Natl Cancer Inst 106(1), djt356 (2014).
    • 3 Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol. 20, 781–810 (2004).
    • 4 Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell 149(6), 1192–1205 (2012).
    • 5 Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat. Rev. Cancer 13(1), 11–26 (2012).
    • 6 Polakis P. Wnt signaling in cancer. Cold Spring Harb. Perspect. Biol 4(5), a008052 (2012).
    • 7 Wu Y, Ginther C, Kim J et al. Expression of Wnt3 activates Wnt/β-catenin pathway and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cells. Mol. Cancer Res. 10(12), 1597–1606 (2012).
    • 8 NIH National Cancer Institute. Combination chemotherapy and bevacizumab with or without PRI-724 in treating patients with newly diagnosed metastatic colorectal cancer. www.cancer.gov/about-cancer/treatment/clinical-trials/search/view?cdrid=771168&version=HealthProfessional&protocolsearchid=9920214.
    • 9 Van Es JH, Clevers H. Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease. Trends Mol. Med. 11(11), 496–502 (2005).
    • 10 Voronkov A, Krauss S. Wnt/beta-catenin signaling and small molecule inhibitors. Curr. Pharm. Des 19(4), 634 (2012).
    • 11 Le PN, Mcdermott JD, Jimeno A. Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol. Ther. 146(0), 1–11 (2015).
    • 12 Kahn M. Can we safely target the WNT pathway?. Nat. Rev. Drug Discov. 13(7), 513–532 (2014).
    • 13 Lee H-J, Zhang X, Zheng JJ. Inhibiting the Wnt signaling pathway with small molecules. In: Targeting the Wnt Pathway in Cancer. Gross KH, Khan M (Eds). Springer, NY, USA, 183–209 (2011).
    • 14 Chen Z, Li J, Li QS et al. Suppression of PPN/MG61 attenuates Wnt/[beta]-catenin signaling pathway and induces apoptosis in human lung cancer. Oncogene 27(24), 3483–3488 (2008).
    • 15 Chen B, Dodge ME, Tang W et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat. Chem. Biol. 5(2), 100–107 (2009). • First report on the small-molecule inhibitor of porcupine.
    • 16 Dodge ME, Moon J, Tuladhar R et al. Diverse chemical scaffolds support direct inhibition of the membrane-bound O-acyltransferase porcupine. J. Biol. Chem. 287(27), 23246–23254 (2012).
    • 17 Wang X, Moon J, Dodge ME et al. The development of highly potent inhibitors for Porcupine. J. Med. Chem. 56(6), 2700–2704 (2013).
    • 18 Liu J, Pan S, Hsieh MH et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc. Natl Acad. Sci. USA 110(50), 20224–20229 (2013). • Development of one of two small-molecule inhibitors of Wnt signaling pathways that are in clinical trials.
    • 19 Proffitt KD, Madan B, Ke Z et al. Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res. 73(2), 502–507 (2013).
    • 20 Duraiswamy AJ, Lee MA, Madan B et al. Discovery and optimization of a porcupine inhibitor. J. Med. Chem. 58(15), 5889–5899 (2015).
    • 21 Riffell JL, Lord CJ, Ashworth A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat. Rev. Drug Discov. 11(12), 923–936 (2012).
    • 22 Huang S-MA, Mishina YM, Liu S. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461(7264), 614–620 (2009). • Discovered the first tankyrase inhibitor.
    • 23 Karlberg T, Markova N, Johansson I et al. Structural basis for the interaction between tankyrase-2 and a potent Wnt-signaling inhibitor. J. Med. Chem. 53(14), 5352–5355 (2010).
    • 24 Nathubhai A, Wood PJ, Lloyd MD, Thompson AS, Threadgill MD. Design and discovery of 2-arylquinazolin-4-ones as potent and selective inhibitors of tankyrases. ACS Med. Chem. Lett. 4(12), 1173–1177 (2013).
    • 25 Haikarainen T, Koivunen J, Narwal M et al. Para-substituted 2-phenyl-3,4-dihydroquinazolin-4-ones as potent and selective tankyrase inhibitors. ChemMedChem 8(12), 1978–1985 (2013).
    • 26 Johannes JW, Almeida L, Barlaam B et al. Pyrimidinone nicotinamide mimetics as selective tankyrase and Wnt pathway inhibitors suitable for in vivo pharmacology. ACS Med. Chem. Lett. 6(3), 254–259 (2015).
    • 27 Shultz MD, Majumdar D, Chin DN et al. Structure–efficiency relationship of [1,2,4]Triazol-3-ylamines as novel nicotinamide isosteres that inhibit tankyrases. J. Med. Chem. 56(17), 7049–7059 (2013).
    • 28 Kirby CA, Cheung A, Fazal A, Shultz MD, Stams T. Structure of human tankyrase 1 in complex with small-molecule inhibitors PJ34 and XAV939. Acta Crystallographica Section F 68(Pt 2), 115–118 (2012).
    • 29 Liscio P, Carotti A, Asciutti S et al. Design, synthesis, crystallographic studies, and preliminary biological appraisal of new substituted triazolo[4,3-b]pyridazin-8-amine derivatives as tankyrase inhibitors. J. Med. Chem. 57(6), 2807–2812 (2014).
    • 30 Larsson EA, Jansson A, Ng FM et al. Fragment-based ligand design of novel potent inhibitors of tankyrases. J. Med. Chem. 56(11), 4497–4508 (2013).
    • 31 Liscio P, Carotti A, Asciutti S et al. Scaffold hopping approach on the route to selective tankyrase inhibitors. Eur. J. Med. Chem. 87(0), 611–623 (2014).
    • 32 Narwal M, Haikarainen T, Fallarero A, Vuorela PM, Lehtiö L. Screening and structural analysis of flavones inhibiting tankyrases. J. Med. Chem. 56(9), 3507–3517 (2013).
    • 33 Narwal M, Venkannagari H, Lehtiö L. Structural basis of selective inhibition of human tankyrases. J. Med. Chem. 55(3), 1360–1367 (2012). • Discovery of non-nicotinamide-binding site for tankyrase inhibitors
    • 34 Lu J, Ma Z, Hsieh J-C et al. Structure–activity relationship studies of small-molecule inhibitors of Wnt response. Bioorg. Med. Chem. Lett. 19(14), 3825–3827 (2009).
    • 35 Lanier M, Schade D, Willems E et al. Wnt inhibition correlates with human embryonic stem cell cardiomyogenesis: a structure–activity relationship study based on inhibitors for the Wnt response. J. Med. Chem. 55(2), 697–708 (2012).
    • 36 Bregman H, Chakka N, Guzman-Perez A et al. Discovery of novel, induced-pocket binding oxazolidinones as potent, selective, and orally bioavailable tankyrase inhibitors. J. Med. Chem. 56(11), 4320–4342 (2013).
    • 37 Huang H, Guzman-Perez A, Acquaviva L et al. Structure-based design of 2-aminopyridine oxazolidinones as potent and selective tankyrase inhibitors. ACS Med. Chem. Lett. 4(12), 1218–1223 (2013).
    • 38 James RG, Davidson KC, Bosch KA et al. WIKI4, a novel inhibitor of tankyrase and Wnt/ss-catenin signaling. PLoS ONE 7(12), e50457 (2012).
    • 39 Haikarainen T, Venkannagari H, Narwal M et al. Structural basis and selectivity of tankyrase inhibition by a Wnt signaling inhibitor WIKI4. PLoS ONE 8(6), e65404 (2013).
    • 40 Waaler J, Machon O, Von Kries JP et al. Novel synthetic antagonists of canonical Wnt signaling inhibit colorectal cancer cell growth. Cancer Res. 71(1), 197–205 (2011).
    • 41 Wessel Stratford E, Daffinrud J, Munthe E et al. The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines. Cancer Med. 3(1), 36–46 (2014).
    • 42 Shultz MD, Kirby CA, Stams T et al. [1,2,4]Triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazoles: antagonists of the Wnt pathway that inhibit tankyrases 1 and 2 via novel adenosine pocket binding. J. Med. Chem. 55(3), 1127–1136 (2012).
    • 43 Waaler J, Machon O, Tumova L et al. A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Res. 72(11), 2822–2832 (2012).
    • 44 Voronkov A, Holsworth DD, Waaler J et al. Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor. J. Med. Chem. 56(7), 3012–3023 (2013).
    • 45 Lau T, Chan E, Callow M et al. A novel tankyrase small-molecule inhibitor suppresses APC mutation–driven colorectal tumor growth. Cancer Res. 73(10), 3132–3144 (2013).
    • 46 Kirubakaran P, Arunkumar P, Premkumar K, Muthusamy K. Sighting of tankyrase inhibitors by structure- and ligand-based screening and in vitro approach. Mol. Biosyst. 10(10), 2699–2712 (2014).
    • 47 Bregman H, Gunaydin H, Gu Y et al. Discovery of a class of novel tankyrase inhibitors that bind to both the nicotinamide pocket and the induced pocket. J. Med. Chem. 56(3), 1341–1345 (2013).
    • 48 Hua Z, Bregman H, Buchanan JL et al. Development of novel dual binders as potent, selective, and orally bioavailable tankyrase inhibitors. J. Med. Chem. 56(24), 10003–10015 (2013).
    • 49 Shultz MD, Cheung AK, Kirby CA et al. Identification of NVP-TNKS656: the use of structure–efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor. J. Med. Chem. 56(16), 6495–6511 (2013).
    • 50 Hao J, Ao A, Zhou L et al. Selective small molecule targeting β-catenin function discovered by in vivo chemical genetic screen. Cell Rep. 4(5), 898–904 (2013).
    • 51 Ashihara E, Kawata E, Nakagawa Y et al. β-catenin small interfering RNA successfully suppressed progression of multiple myeloma in a mouse model. Clin. Cancer. Res. 15(8), 2731–2738 (2009).
    • 52 Scholer-Dahirel A, Schlabach MR, Loo A et al. Maintenance of adenomatous polyposis coli (APC)-mutant colorectal cancer is dependent on Wnt/β-catenin signaling. Proc. Natl Acad. Sci. USA 108(41), 17135–17140 (2011).
    • 53 Lepourcelet M, Chen Y-NP, France DS et al. Small-molecule antagonists of the oncogenic Tcf/β-catenin protein complex. Cancer Cell 5(1), 91–102 (2004). • Identified the inhibitors of β-catenin/T-cell factor interaction.
    • 54 Lee M-A, Kim WK, Park HJ, Kang SS, Lee SK. Anti-proliferative activity of hydnocarpin, a natural lignan, is associated with the suppression of Wnt/β-catenin signaling pathway in colon cancer cells. Bioorg. Med. Chem. Lett. 23(20), 5511–5514 (2013).
    • 55 Chen Z, Venkatesan AM, Dehnhardt CM et al. 2,4-Diamino-quinazolines as inhibitors of β-catenin/Tcf-4 pathway: Potential treatment for colorectal cancer. Bioorg. Med. Chem. Lett. 19(17), 4980–4983 (2009).
    • 56 Park CH, Chang JY, Hahm ER, Park S, Kim H-K, Yang CH. Quercetin, a potent inhibitor against β-catenin/Tcf signaling in SW480 colon cancer cells. Biochem. Biophys. Res. Commun. 328(1), 227–234 (2005).
    • 57 Yu B, Huang Z, Zhang M, Dillard DR, Ji H. Rational design of small-molecule inhibitors for β-catenin/T-cell factor protein–protein interactions by bioisostere replacement. ACS Chem. Biol. 8(3), 524–529 (2013).
    • 58 Zhang M, Catrow JL, Ji H. High-throughput selectivity assays for small-molecule inhibitors of β-catenin/T-cell factor protein–protein interactions. ACS Med. Chem. Lett. 4(2), 306–311 (2013).
    • 59 Catrow JL, Zhang Y, Zhang M, Ji H. Discovery of selective small-molecule inhibitors for the β-Catenin/T-Cell factor protein–protein interaction through the optimization of the acyl hydrazone moiety. J. Med. Chem. 58(11), 4678–4692 (2015).
    • 60 Lu D, Liu JX, Endo T et al. Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/β-catenin pathway. PLoS ONE 4(12), e8294 (2009).
    • 61 Wall I, Schmidt-Wolf IGH. Effect of Wnt inhibitors in pancreatic cancer. Anticancer Res. 34(10), 5375–5380 (2014).
    • 62 Emami KH, Nguyen C, Ma H et al. A small molecule inhibitor of β-catenin/cyclic AMP response element-binding protein transcription. Proc. Natl Acad. Sci. USA 101(34), 12682–12687 (2004). • Identified a specific inhibitor of binding cyclic AMP response element-binding protein, which is also in clinical trial.
    • 63 Jin G, Lu D, Yao S et al. Amide derivatives of ethacrynic acid: synthesis and evaluation as antagonists of Wnt/β-catenin signaling and CLL cell survival. Bioorg. Med. Chem. Lett. 19(3), 606–609 (2009).
    • 64 Arensman MD, Telesca D, Lay AR et al. The CREB-binding protein inhibitor ICG-001 suppresses pancreatic cancer growth.Mol. Cancer Ther. 13(10), 2303–2314 (2014).
    • 65 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. Proc. Natl Acad. Sci. USA 108(15), 5954–5963 (2011).
    • 66 Bilir B, Kucuk O, Moreno CS. Wnt signaling blockage inhibits cell proliferation and migration, and induces apoptosis in triple-negative breast cancer cells. J. Transl. Med 11(1), 280 (2013).
    • 67 Zhang W, Sviripa V, Kril LM et al. Fluorinated N,N-Dialkylaminostilbenes for Wnt Pathway Inhibition and Colon Cancer Repression. J. Med. Chem. 54(5), 1288–1297 (2011).
    • 68 Schmeel FC, Schmeel LC, Kim Y, Schmidt-Wolf IG. Piceatannol exhibits selective toxicity to multiple myeloma cells and influences the Wnt/beta-catenin pathway. Hematol. Oncol. 32(4), 197–204 (2014).
    • 69 Albring KF, Weidemüller J, Mittag S et al. Berberine acts as a natural inhibitor of Wnt/β-catenin signaling-Identification of more active 13-arylalkyl derivatives. Biofactors 39(6), 652–662 (2013).
    • 70 Chen M, Wang J, Lu J et al. The anti-helminthic niclosamide inhibits Wnt/frizzled1 signaling. Biochemistry 48(43), 10267–10274 (2009).
    • 71 Gödeke J, Maier S, Eichenmüller M, Müller-Höcker J, Von Schweinitz D, Kappler R. Epigallocatechin-3-gallate inhibits hepatoblastoma growth by reactivating the Wnt inhibitor SFRP1. Nutr. Cancer 65(8), 1200–1207 (2013).
    • 72 Aguilera O, Peña C, García JM et al. The Wnt antagonist DICKKOPF-1 gene is induced by 1α, 25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells. Carcinogenesis 28(9), 1877–1884 (2007).
    • 73 Gustafson B, Eliasson B, Smith U. Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: a link with osteogenesis. Diabetologia 53(3), 536–540 (2010).
    • 74 Gilbert AM, Bursavich MG, Alon N et al. Hit to lead studies on (hetero)arylpyrimidines – agonists of the canonical Wnt-β-catenin cellular messaging system. Bioorg. Med. Chem. Lett. 20(1), 366–370 (2010).
    • 75 Shan J, Shi D-L, Wang J, Zheng J. Identification of a specific inhibitor of the dishevelled PDZ domain. Biochemistry 44(47), 15495–15503 (2005).
    • 76 Fujii N, You L, Xu Z et al. An antagonist of dishevelled protein-protein interaction suppresses β-catenin-dependent tumor cell growth. Cancer Res. 67(2), 573–579 (2007).
    • 77 Grandy D, Shan J, Zhang X et al. Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled. J. Biol. Chem. 284(24), 16256–16263 (2009).
    • 78 Thorne CA, Hanson AJ, Schneider J et al. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nat. Chem. Biol. 6(11), 829–836 (2010). • Identified a potent inhibitor of Wnt signaling by activating casein kinase 1-α.
    • 79 De Robertis A, Valensin S, Rossi M et al. Identification and characterization of a small-molecule inhibitor of Wnt signaling in glioblastoma cells. Mol. Cancer Ther. 12(7), 1180–1189 (2013).
    • 80 De Robertis A, Mennillo F, Rossi M et al. Human sarcoma growth is sensitive to small-molecule mediated AXIN stabilization. PLoS ONE 9(5), e97847 (2014).
    • 81 Zhang J, Kong L-M, Zhan R et al. Two natural ent-kauranoids as novel Wnt signaling inhibitors. Nat. Prod. Bioprospect. 4(3), 135–140 (2014).
    • 82 Koval AV, Vlasov P, Shichkova P et al. Anti-leprosy drug clofazimine inhibits growth of triple-negative breast cancer cells via inhibition of canonical Wnt signaling. Biochem. Pharmacol. 87(4), 571–578 (2014).
    • 83 Soldi R, Horrigan SK, Cholody MW et al. Design, synthesis, and biological evaluation of a series of anthracene-9,10-dione dioxime β-catenin pathway inhibitors. J. Med. Chem. 58(15), 5854–5862 (2015).
    • 84 De Vicente J, Tivitmahaisoon P, Berry P et al. Fragment-based drug design of novel pyranopyridones as cell active and orally bioavailable tankyrase inhibitors. ACS Med. Chem. Lett. 6(9), 1019–1024 (2015).
    • 85 Higuchi Y, Nguyen C, Yasuda S-Y, Mcmillan M, Hasegawa K, Kahn M. Specific direct small molecule p300/β-catenin antagonists maintain stem cell potency. Curr. Mol. Pharmacol. 8, 1–8 (2015).
    • 86 Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic [bgr]-catenin signalling prevents anti-tumour immunity. Nature 523(7559), 231–235 (2015). •• Revealed a correlation between activation of Wnt/β-catenin signaling pathway and absence of a T-cell gene expression signature.