7O6X

Tankyrase 2 in complex with an inhibitor (OM-153)

This is a non-PDB format compatible entry.

Summary for 7O6X

• Entry DOI: 10.2210/pdb7o6x/pdb
• Descriptor: Poly [ADP-ribose] polymerase tankyrase-2, N-[3-[5-(5-ethoxypyridin-2-yl)-4-(2-fluorophenyl)-1,2,4-triazol-3-yl]cyclobutyl]quinoxaline-5-carboxamide, ZINC ION, ... (5 entities in total)
• Functional Keywords: inhibitor, complex, poly-adp-ribosylation, enzyme, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 50842.07

Authors

Sowa, S.T.,Lehtio, L. (deposition date: 2021-04-12, release date: 2022-01-12, Last modification date: 2024-01-31)

Primary citation

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.,Nazare, M.,Lehtio, L.,Waaler, J.,Krauss, S.
Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II.
J.Med.Chem., 64:17936-17949, 2021

PubMed 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 (OM-1700), further structure-activity relationship analyses of East-, South- and West-single-point alterations and hybrids identified compound (OM-153). Compound showed picomolar IC 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 induced dose-dependent biomarker engagement and reduced cell growth in the colon cancer cell line COLO 320DM.

PubMed: 34878777
DOI: 10.1021/acs.jmedchem.1c01264

Experimental method

X-RAY DIFFRACTION (2.2 Å)