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Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II

[Image: see text] 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 canc...

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Detalles Bibliográficos
Autores principales: Leenders, Ruben G. G., Brinch, Shoshy Alam, Sowa, Sven T., Amundsen-Isaksen, Enya, Galera-Prat, Albert, Murthy, Sudarshan, Aertssen, Sjoerd, Smits, Johannes N., Nieczypor, Piotr, Damen, Eddy, Wegert, Anita, Nazaré, Marc, Lehtiö, Lari, Waaler, Jo, Krauss, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713164/
https://www.ncbi.nlm.nih.gov/pubmed/34878777
http://dx.doi.org/10.1021/acs.jmedchem.1c01264
Descripción
Sumario:[Image: see text] 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 IC(50) 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.