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| Item Type: | Article |
|---|---|
| Title: | Development of a 1,2,4-triazole-based lead tankyrase inhibitor: part II |
| Creators Name: | Leenders, R.G.G., Brinch, S.A., Sowa, S.T., Amundsen-Isaksen, E., Galera-Prat, A., Murthy, S., Aertssen, S., Smits, J.N., Nieczypor, P., Damen, E., Wegert, A., Nazaré, M., Lehtiö, L., Waaler, J. and Krauss, S. |
| Abstract: | 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 IC50 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. |
| Keywords: | Drug Development, Enzyme Inhibitors, Hippo Signaling Pathway, Structure-Activity Relationship, Tankyrases, Triazoles, Wnt Signaling Pathway, Animals, Mice |
| Source: | Journal of Medicinal Chemistry |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Volume: | 64 |
| Number: | 24 |
| Page Range: | 17936-17949 |
| Date: | 23 December 2021 |
| Official Publication: | https://doi.org/10.1021/acs.jmedchem.1c01264 |
| PubMed: | View item in PubMed |
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