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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)
Related entries: 5nsx, 5nt0, 5nt4, 5nut, 5nvc, 5nve, 5nvh, 5nwb, 5nwc, 5nwd, 5nwg, 5nxe, 5ows, 5owt

Cited: 7 times
EuropePMC logo PMID: 29374194

Abstract

Tankyrases (TNKSs) are enzymes specialized in catalyzing poly-ADP-ribosylation of target proteins. Several studies have validated TNKSs as anti-cancer drug targets due to their regulatory role in Wnt/β-catenin pathway. Recently a lot of effort has been put into developing more potent and selective TNKS inhibitors and optimizing them towards anti-cancer agents. We noticed that some 2-phenylquinazolinones (2-PQs) reported as CDK9 inhibitors were similar to previously published TNKS inhibitors. In this study, we profiled this series of 2-PQs against TNKS and selected kinases that are involved in the Wnt/β-catenin pathway. We found that they were much more potent TNKS inhibitors than they were CDK9/kinase inhibitors. We evaluated the compound selectivity to tankyrases over the ARTD enzyme family and solved co-crystal structures of the compounds with TNKS2. Comparative structure-based studies of the catalytic domain of TNKS2 with selected CDK9 inhibitors and docking studies of the inhibitors with two kinases (CDK9 and Akt) revealed important structural features, which could explain the selectivity of the compounds towards either tankyrases or kinases. We also discovered a compound, which was able to inhibit tankyrases, CDK9 and Akt kinases with equal µM potency.

Reviews citing this publication (1)

  1. Privileged Scaffolds for Potent and Specific Inhibitors of Mono-ADP-Ribosylating PARPs. Nizi MG, Sarnari C, Tabarrini O. Molecules 28 5849 (2023)

Articles citing this publication (6)

  1. Discovery of Novel Tankyrase Inhibitors through Molecular Docking-Based Virtual Screening and Molecular Dynamics Simulation Studies. Berishvili VP, Kuimov AN, Voronkov AE, Radchenko EV, Kumar P, Choonara YE, Pillay V, Kamal A, Palyulin VA. Molecules 25 E3171 (2020)
  2. Discovery of Novel Inhibitor for WNT/β-Catenin Pathway by Tankyrase 1/2 Structure-Based Virtual Screening. Li B, Liang J, Lu F, Zeng G, Zhang J, Ma Y, Liu P, Wang Q, Zhou Q, Chen L. Molecules 25 E1680 (2020)
  3. Bioinformatic Analysis of the Nicotinamide Binding Site in Poly(ADP-Ribose) Polymerase Family Proteins. Manasaryan G, Suplatov D, Pushkarev S, Drobot V, Kuimov A, Švedas V, Nilov D. Cancers (Basel) 13 1201 (2021)
  4. Structural basis of tankyrase activation by polymerization. Pillay N, Mariotti L, Zaleska M, Inian O, Jessop M, Hibbs S, Desfosses A, Hopkins PCR, Templeton CM, Beuron F, Morris EP, Guettler S. Nature 612 162-169 (2022)
  5. [1,2,4]Triazolo[3,4-b]benzothiazole Scaffold as Versatile Nicotinamide Mimic Allowing Nanomolar Inhibition of Different PARP Enzymes. Murthy S, Nizi MG, Maksimainen MM, Massari S, Alaviuhkola J, Lippok BE, Vagaggini C, Sowa ST, Galera-Prat A, Ashok Y, Venkannagari H, Prunskaite-Hyyryläinen R, Dreassi E, Lüscher B, Korn P, Tabarrini O, Lehtiö L. J Med Chem 66 1301-1320 (2023)
  6. 3,4,3'-Tri-O-methylellagic acid as an anticancer agent: in vitro and in silico studies. Wardana AP, Abdjan MI, Aminah NS, Fahmi MZ, Siswanto I, Kristanti AN, Saputra MA, Takaya Y. RSC Adv 12 29884-29891 (2022)


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