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para-Substituted 2-phenyl-3,4-dihydroquinazolin-4-ones as potent and selective tankyrase inhibitors.

Haikarainen T, Koivunen J, Narwal M, Venkannagari H, Obaji E, Joensuu P, Pihlajaniemi T, Lehtiö L
ChemMedChem 8 1978-85 (2013)
Related entries: 4bu3, 4bu5, 4bu7, 4bu8, 4bu9, 4bua, 4bud, 4bue, 4buf, 4bui, 4bus, 4but, 4buu, 4buv, 4buw, 4bux, 4buy

Cited: 13 times
EuropePMC logo PMID: 24130191

Abstract

Human tankyrases are attractive drug targets, especially for the treatment of cancer. We identified a set of highly potent tankyrase inhibitors based on a 2-phenyl-3,4-dihydroquinazolin-4-one scaffold. Substitutions at the para position of the scaffold's phenyl group were evaluated as a strategy to increase potency and improve selectivity. The best compounds displayed single-digit nanomolar potencies, and profiling against several human diphtheria-toxin-like ADP-ribosyltransferases revealed that a subset of these compounds are highly selective tankyrase inhibitors. The compounds also effectively inhibit Wnt signaling in HEK293 cells. The binding mode of all inhibitors was studied by protein X-ray crystallography. This allowed us to establish a structural basis for the development of highly potent and selective tankyrase inhibitors based on the 2-phenyl-3,4-dihydroquinazolin-4-one scaffold and outline a rational approach to the modification of other inhibitor scaffolds that bind to the nicotinamide site of the catalytic domain.

Reviews citing this publication (5)

  1. Tankyrases: structure, function and therapeutic implications in cancer. Haikarainen T, Krauss S, Lehtio L. Curr. Pharm. Des. 20 6472-6488 (2014)
  2. 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)
  3. 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)
  4. Small-molecule inhibitors of Wnt signaling pathway: towards novel anticancer therapeutics. Zheng S, Liu J, Wu Y, Huang TL, Wang G. Future Med Chem 7 2485-2505 (2015)
  5. Inhibition of poly(adenosine diphosphate-ribose) polymerase using quinazolinone nucleus. Hemalatha K, Madhumitha G. Appl. Microbiol. Biotechnol. 100 7799-7814 (2016)

Articles citing this publication (8)

  1. Pyrimidinone nicotinamide mimetics as selective tankyrase and wnt pathway inhibitors suitable for in vivo pharmacology. Johannes JW, Almeida L, Barlaam B, Boriack-Sjodin PA, Casella R, Croft RA, Dishington AP, Gingipalli L, Gu C, Hawkins JL, Holmes JL, Howard T, Huang J, Ioannidis S, Kazmirski S, Lamb ML, McGuire TM, Moore JE, Ogg D, Patel A, Pike KG, Pontz T, Robb GR, Su N, Wang H, Wu X, Zhang HJ, Zhang Y, Zheng X, Wang T. ACS Med Chem Lett 6 254-259 (2015)
  2. Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation. Bhardwaj A, Yang Y, Ueberheide B, Smith S. Nat Commun 8 2214 (2017)
  3. Characterization of the DNA dependent activation of human ARTD2/PARP2. Obaji E, Haikarainen T, Lehtiö L. Sci Rep 6 34487 (2016)
  4. Discovery of potent and selective nonplanar tankyrase inhibiting nicotinamide mimics. Nkizinkiko Y, Suneel Kumar BV, 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)
  5. Scaffold hopping approach on the route to selective tankyrase inhibitors. Liscio P, Carotti A, Asciutti S, Ferri M, Pires MM, Valloscuro S, Ziff J, Clark NR, Macchiarulo A, Aaronson SA, Pellicciari R, Camaioni E. Eur J Med Chem 87 611-623 (2014)
  6. First body of evidence suggesting a role of a tankyrase-binding motif (TBM) of vinculin (VCL) in epithelial cells. Vilchez Larrea S, Valsecchi WM, Fernández Villamil SH, Lafon Hughes LI. PeerJ 9 e11442 (2021)
  7. 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)
  8. Multiple E3 ligases control tankyrase stability and function. Perrard J, Smith S. Nat Commun 14 7208 (2023)


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