Development of a 1,2,4-triazole-based lead tankyrase inhibitor : part II
Krauss, Stefan; 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 (2021-12-08)
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., & Krauss, S. (2021). Development of a 1,2,4-triazole-based lead tankyrase inhibitor: Part ii. Journal of Medicinal Chemistry, 64(24), 17936–17949. https://doi.org/10.1021/acs.jmedchem.1c01264
© 2021 The Authors. Published by American Chemical Society. This is an open access article published under Creatice Commons Attribution 4.0 International license (CC BY 4.0).
https://creativecommons.org/licenses/by/4.0/
https://urn.fi/URN:NBN:fi-fe2021121761685
Tiivistelmä
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 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.
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