4MSG

Crystal structure of tankyrase 1 with compound 22

Summary for 4MSG

• Entry DOI: 10.2210/pdb4msg/pdb
• Related: 4I9I 4MSK
• Descriptor: Tankyrase-1, ZINC ION, 3-[(4-oxo-3,4-dihydroquinazolin-2-yl)sulfanyl]-N-[trans-4-(5-phenyl-1,3,4-oxadiazol-2-yl)cyclohexyl]propanamide, ... (4 entities in total)
• Functional Keywords: tankyrase, parp, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: O95271
• Total number of polymer chains: 2
• Total formula weight: 51164.61

Authors

Huang, X. (deposition date: 2013-09-18, release date: 2013-12-25, Last modification date: 2024-02-28)

Primary citation

Hua, Z.,Bregman, H.,Buchanan, J.L.,Chakka, N.,Guzman-Perez, A.,Gunaydin, H.,Huang, X.,Gu, Y.,Berry, V.,Liu, J.,Teffera, Y.,Huang, L.,Egge, B.,Emkey, R.,Mullady, E.L.,Schneider, S.,Andrews, P.S.,Acquaviva, L.,Dovey, J.,Mishra, A.,Newcomb, J.,Saffran, D.,Serafino, R.,Strathdee, C.A.,Turci, S.M.,Stanton, M.,Wilson, C.,Dimauro, E.F.
Development of novel dual binders as potent, selective, and orally bioavailable tankyrase inhibitors.
J.Med.Chem., 56:10003-10015, 2013

PubMed Abstract: Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting β-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.

PubMed: 24294969
DOI: 10.1021/jm401317z

Experimental method

X-RAY DIFFRACTION (1.8 Å)