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Development of a 1,2,4-triazole-based lead tankyrase inhibitor: part II

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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. and Brinch, S.A. and Sowa, S.T. and Amundsen-Isaksen, E. and Galera-Prat, A. and Murthy, S. and Aertssen, S. and Smits, J.N. and Nieczypor, P. and Damen, E. and Wegert, A. and Nazaré, M. and Lehtiö, L. and 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
Publisher:American Chemical Society
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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