4N4T

Co-crystal structure of tankyrase 1 with compound 3 [(4S)-3-{4-[6-amino-5-(pyrimidin-2-yl)pyridin-3-yl]phenyl}-5,5-dimethyl-4-phenyl-1,3-oxazolidin-2-one]

Summary for 4N4T

• Entry DOI: 10.2210/pdb4n4t/pdb
• Related: 4K4F 4N3R 4N4V
• Descriptor: Tankyrase-1, ZINC ION, (4S)-3-{4-[6-amino-5-(pyrimidin-2-yl)pyridin-3-yl]phenyl}-5,5-dimethyl-4-phenyl-1,3-oxazolidin-2-one, ... (4 entities in total)
• Functional Keywords: tankyrase, parp, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mus musculus (mouse)
• Cellular location: Cytoplasm (By similarity): Q6PFX9
• Total number of polymer chains: 2
• Total formula weight: 51088.47

Authors

Huang, X. (deposition date: 2013-10-08, release date: 2013-12-11, Last modification date: 2024-02-28)

Primary citation

Huang, H.,Guzman-Perez, A.,Acquaviva, L.,Berry, V.,Bregman, H.,Dovey, J.,Gunaydin, H.,Huang, X.,Huang, L.,Saffran, D.,Serafino, R.,Schneider, S.,Wilson, C.,DiMauro, E.F.
Structure-based design of 2-aminopyridine oxazolidinones as potent and selective tankyrase inhibitors.
ACS Med Chem Lett, 4:1218-1223, 2013

PubMed Abstract: Aberrant activation of the Wnt pathway has been implicated in the development and formation of many cancers. TNKS inhibition has been shown to antagonize Wnt signaling via Axin stabilization in APC mutant colon cancer cell lines. We employed structure-based design to identify a series of 2-aminopyridine oxazolidinones as potent and selective TNKS inhibitors. These compounds exhibited good enzyme and cell potency as well as selectivity over other PARP isoforms. Co-crystal structures of these 2-aminopyridine oxazolidinones complexed to TNKS reveal an induced-pocket binding mode that does not involve interactions with the nicotinamide binding pocket. Oral dosing of lead compounds 3 and 4 resulted in significant effects on several Wnt-pathway biomarkers in a three day DLD-1 mouse tumor PD model.

PubMed: 24900633
DOI: 10.1021/ml4003315

Experimental method

X-RAY DIFFRACTION (2.315 Å)