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Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity.

Narwal M, Koivunen J, Haikarainen T, Obaji E, Legala OE, Venkannagari H, Joensuu P, Pihlajaniemi T, Lehtiö L
J Med Chem 56 7880-9 (2013)
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Cited: 28 times
EuropePMC logo PMID: 24116873

Abstract

Tankyrases are ADP-ribosyltransferases that play key roles in various cellular pathways, including the regulation of cell proliferation, and thus, they are promising drug targets for the treatment of cancer. Flavones have been shown to inhibit tankyrases and we report here the discovery of more potent and selective flavone derivatives. Commercially available flavones with single substitutions were used for structure-activity relationship studies, and cocrystal structures of the 18 hit compounds were analyzed to explain their potency and selectivity. The most potent inhibitors were also tested in a cell-based assay, which demonstrated that they effectively antagonize Wnt signaling. To assess selectivity, they were further tested against a panel of homologous human ADP-ribosyltransferases. The most effective compound, 22 (MN-64), showed 6 nM potency against tankyrase 1, isoenzyme selectivity, and Wnt signaling inhibition. This work forms a basis for rational development of flavones as tankyrase inhibitors and guides the development of other structurally related inhibitors.

Articles - 4l10 mentioned but not cited (1)

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Reviews citing this publication (10)

  1. Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities. Xu X, Zhang M, Xu F, Jiang S. Mol Cancer 19 165 (2020)
  2. Tankyrases: structure, function and therapeutic implications in cancer. Haikarainen T, Krauss S, Lehtio L. Curr Pharm Des 20 6472-6488 (2014)
  3. Tetrazoles via Multicomponent Reactions. Neochoritis CG, Zhao T, Dömling A. Chem Rev 119 1970-2042 (2019)
  4. Regulation of Wnt/β-catenin signalling by tankyrase-dependent poly(ADP-ribosyl)ation and scaffolding. Mariotti L, Pollock K, Guettler S. Br J Pharmacol 174 4611-4636 (2017)
  5. Flavonoids and Wnt/β-catenin signaling: potential role in colorectal cancer therapies. Amado NG, Predes D, Moreno MM, Carvalho IO, Mendes FA, Abreu JG. Int J Mol Sci 15 12094-12106 (2014)
  6. Wnt Drug Discovery: Weaving Through the Screens, Patents and Clinical Trials. Lu B, Green BA, Farr JM, Lopes FC, Van Raay TJ. Cancers (Basel) 8 E82 (2016)
  7. A survey of the role of nitrile groups in protein-ligand interactions. Wang Y, Du Y, Huang N. Future Med Chem 10 2713-2728 (2018)
  8. Concepts and Molecular Aspects in the Polypharmacology of PARP-1 Inhibitors. Passeri D, Camaioni E, Liscio P, Sabbatini P, Ferri M, Carotti A, Giacchè N, Pellicciari R, Gioiello A, Macchiarulo A. ChemMedChem 11 1219-1226 (2016)
  9. Recent advances in the structure-based rational design of TNKSIs. Zhan P, Song Y, Itoh Y, Suzuki T, Liu X. Mol Biosyst 10 2783-2799 (2014)
  10. A New Wave of Targeting 'Undruggable' Wnt Signaling for Cancer Therapy: Challenges and Opportunities. Park WJ, Kim MJ. Cells 12 1110 (2023)

Articles citing this publication (17)

  1. Angiomotin stabilization by tankyrase inhibitors antagonizes constitutive TEAD-dependent transcription and proliferation of human tumor cells with Hippo pathway core component mutations. Troilo A, Benson EK, Esposito D, Garibsingh RA, Reddy EP, Mungamuri SK, Aaronson SA. Oncotarget 7 28765-28782 (2016)
  2. 3D-QSAR, Docking, ADME/Tox studies on Flavone analogs reveal anticancer activity through Tankyrase inhibition. Alam S, Khan F, Khan F. Sci Rep 9 5414 (2019)
  3. Derricin and derricidin inhibit Wnt/β-catenin signaling and suppress colon cancer cell growth in vitro. Fonseca BF, Predes D, Cerqueira DM, Reis AH, Amado NG, Cayres MC, Kuster RM, Oliveira FL, Mendes FA, Abreu JG. PLoS One 10 e0120919 (2015)
  4. Structural insights into SAM domain-mediated tankyrase oligomerization. DaRosa PA, Ovchinnikov S, Xu W, Klevit RE. Protein Sci 25 1744-1752 (2016)
  5. Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases. Kumpan K, Nathubhai A, Zhang C, Wood PJ, Lloyd MD, Thompson AS, Haikarainen T, Lehtiö L, Threadgill MD. Bioorg Med Chem 23 3013-3032 (2015)
  6. Biflavone Ginkgetin, a Novel Wnt Inhibitor, Suppresses the Growth of Medulloblastoma. Ye ZN, Yu MY, Kong LM, Wang WH, Yang YF, Liu JQ, Qiu MH, Li Y. Nat Prod Bioprospect (2015)
  7. Discovery of potent and selective nonplanar tankyrase inhibiting nicotinamide mimics. Nkizinkiko Y, Suneel Kumar BVS, Jeankumar VU, Haikarainen T, Koivunen J, Madhuri C, Yogeeswari P, Venkannagari H, Obaji E, Pihlajaniemi T, Sriram D, Lehtiö L. Bioorg Med Chem 23 4139-4149 (2015)
  8. 2-Phenylquinazolinones as dual-activity tankyrase-kinase inhibitors. Nkizinkiko Y, Desantis J, Koivunen J, Haikarainen T, Murthy S, Sancineto L, Massari S, Ianni F, Obaji E, Loza MI, Pihlajaniemi T, Brea J, Tabarrini O, Lehtiö L. Sci Rep 8 1680 (2018)
  9. Me3 Si-SiMe2 [oCON(iPr)2 -C6 H4 ]: An Unsymmetrical Disilane Reagent for Regio- and Stereoselective Bis-Silylation of Alkynes. Xiao P, Cao Y, Gui Y, Gao L, Song Z. Angew Chem Int Ed Engl 57 4769-4773 (2018)
  10. Molecular Dynamics Study of Conformational Changes of Tankyrase 2 Binding Subsites upon Ligand Binding. Hirano Y, Okimoto N, Fujita S, Taiji M. ACS Omega 6 17609-17620 (2021)
  11. Synthesis, spectroscopic, dielectric, molecular docking and DFT studies of (3E)-3-(4-methylbenzylidene)-3,4-dihydro-2H-chromen-2-one: an anticancer agent. Beena T, Sudha L, Nataraj A, Balachandran V, Kannan D, Ponnuswamy MN. Chem Cent J 11 6 (2017)
  12. Tankyrase Inhibitor for Cardiac Tissue Regeneration: an In-silico Approach. Hosseini FS, Amanlou A, Amanlou M. Iran J Pharm Res 20 315-328 (2021)
  13. AIDDISON: Empowering Drug Discovery with AI/ML and CADD Tools in a Secure, Web-Based SaaS Platform. Rusinko A, Rezaei M, Friedrich L, Buchstaller HP, Kuhn D, Ghogare A. J Chem Inf Model 64 3-8 (2024)
  14. AIEE-Active Flavones as a Promising Tool for the Real-Time Tracking of Uptake and Distribution in Live Zebrafish. Wu Y, He Y, Luo H, Jin T, He F. Int J Mol Sci 24 10183 (2023)
  15. Combinatorial Virtual Screening Revealed a Novel Scaffold for TNKS Inhibition to Combat Colorectal Cancer. Chang CC, Pan SF, Wu MH, Cheng CT, Su YR, Jiang SJ, Hsu HJ. Biomedicines 10 143 (2022)
  16. High-throughput screen to identify compounds that prevent or target telomere loss in human cancer cells. Wilson C, Murnane JP. NAR Cancer 4 zcac029 (2022)
  17. S-SCAM inhibits Axin-dependent synaptic function of GSK3β in a sex-dependent manner. Kearney G, Grau D, Nieves Torres D, Shin SM, Lee SH. Sci Rep 12 4090 (2022)


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