| Autor: |
Krauss, S. (Stefan), Leenders, R. G. (Ruben G. G.), Brinch, S. A. (Shoshy Alam), Sowa, S. T. (Sven T.), Amundsen-Isaksen, E. (Enya), Galera-Prat, A. (Albert), Murthy, S. (Sudarshan), Aertssen, S. (Sjoerd), Smits, J. N. (Johannes N.), Nieczypor, P. (Piotr), Damen, E. (Eddy), Wegert, A. (Anita), Nazaré, M. (Marc), Lehtiö, L. (Lari), Waaler, J. (Jo) |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Popis: |
Tankyrase 1 and 2 (TNKS1/2) catalyze post-translational modification by poly-ADP-ribosylation of a plethora of target proteins. In this function, TNKS1/2 also impact the WNT/β-catenin and Hippo signaling pathways that are involved in numerous human disease conditions including cancer. Targeting TNKS1/2 with small-molecule inhibitors shows promising potential to modulate the involved pathways, thereby potentiating disease intervention. Based on our 1,2,4-triazole-based lead compound 1 (OM-1700), further structure–activity relationship analyses of East-, South- and West-single-point alterations and hybrids identified compound 24 (OM-153). Compound 24 showed picomolar IC₅₉ inhibition in a cellular (HEK293) WNT/β-catenin signaling reporter assay, no off-target liabilities, overall favorable absorption, distribution, metabolism, and excretion (ADME) properties, and an improved pharmacokinetic profile in mice. Moreover, treatment with compound 24 induced dose-dependent biomarker engagement and reduced cell growth in the colon cancer cell line COLO 320DM. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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