Discovery and Optimization of 2‑Arylquinazolin-4-ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity
Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological targets that recently gained interest for anticancer therapy in Wnt pathway dependent tumors. 2-Aryl-quinazolinones were identified and optimized into potent tankyrase inhibitors through SAR exploration around the quinazolinone core and the...
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| Veröffentlicht in: | Journal of medicinal chemistry 2019-09, Vol.62 (17), p.7897-7909 |
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| container_title | Journal of medicinal chemistry |
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| creator | Buchstaller, Hans-Peter Anlauf, Uwe Dorsch, Dieter Kuhn, Daniel Lehmann, Martin Leuthner, Birgitta Musil, Djordje Radtki, Daniela Ritzert, Claudio Rohdich, Felix Schneider, Richard Esdar, Christina |
| description | Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological targets that recently gained interest for anticancer therapy in Wnt pathway dependent tumors. 2-Aryl-quinazolinones were identified and optimized into potent tankyrase inhibitors through SAR exploration around the quinazolinone core and the 4′-position of the phenyl residue. These efforts were supported by analysis of TNKS X-ray and WaterMap structures and resulted in compound 5k, a potent, selective tankyrase inhibitor with favorable pharmacokinetic properties. The X-ray structure of 5k in complex with TNKS1 was solved and confirmed the design hypothesis. Modulation of Wnt pathway activity was demonstrated with this compound in a colorectal xenograft model in vivo. |
| doi_str_mv | 10.1021/acs.jmedchem.9b00656 |
| format | Article |
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Med. Chem</addtitle><date>2019-09-12</date><risdate>2019</risdate><volume>62</volume><issue>17</issue><spage>7897</spage><epage>7909</epage><pages>7897-7909</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological targets that recently gained interest for anticancer therapy in Wnt pathway dependent tumors. 2-Aryl-quinazolinones were identified and optimized into potent tankyrase inhibitors through SAR exploration around the quinazolinone core and the 4′-position of the phenyl residue. These efforts were supported by analysis of TNKS X-ray and WaterMap structures and resulted in compound 5k, a potent, selective tankyrase inhibitor with favorable pharmacokinetic properties. The X-ray structure of 5k in complex with TNKS1 was solved and confirmed the design hypothesis. 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| title | Discovery and Optimization of 2‑Arylquinazolin-4-ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity |
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