RT Journal Article
T1 2-Phenylquinazolinones as dual-activity tankyrase-kinase inhibitors
A1 Nkizinkiko, Yves
A1 Desantis, Jenny
A1 Koivunen, Jarkko
A1 Haikarainen, Teemu
A1 Murthy, Sudarshan
A1 Sancineto, Luca
A1 Massari, Serena
A1 Ianni, Federica
A1 Obaji, Ezeogo
A1 Loza García, María Isabel
A1 Pihlajaniemi, Taina
A1 Brea Floriani, José Manuel
A1 Tabarrini, Oriana
A1 Lehtiö, Lari
AB 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.
PB Nature
YR 2018
FD 2018-01-26
LK https://hdl.handle.net/10347/45513
UL https://hdl.handle.net/10347/45513
LA eng
NO Nkizinkiko, Y., Desantis, J., Koivunen, J. et al. 2-Phenylquinazolinones as dual-activity tankyrase-kinase inhibitors. Sci Rep 8, 1680 (2018). https://doi.org/10.1038/s41598-018-19872-3
DS Minerva
RD 28 abr 2026