4J1Z

Tankyrase 2 in complex with 4-chloro-1,2-dihydrophatalzin-one

Summary for 4J1Z

• Entry DOI: 10.2210/pdb4j1z/pdb
• Related: 4J21 4J22
• Descriptor: Tankyrase-2, ZINC ION, SULFATE ION, ... (5 entities in total)
• Functional Keywords: catalytic fragment, parp, adp-ribosylation, ank repeat, glycosyltransferase, membrane, mrna transport, nad, telomere, transferase, translocation, wnt-signalling, ribosylation
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q9H2K2
• Total number of polymer chains: 2
• Total formula weight: 48862.64

Authors

Jansson, A.E. (deposition date: 2013-02-03, release date: 2013-07-10, Last modification date: 2023-11-08)

Primary citation

Larsson, E.A.,Jansson, A.E.,Ng, F.M.,Then, S.W.,Panicker, R.,Liu, B.,Sangthongpitag, K.,Pendharkar, V.,Tai, S.J.,Hill, J.,Dan, C.,Ho, S.Y.,Cheong, W.W.,Poulsen, A.,Blanchard, S.,Lin, G.R.,Alam, J.,Keller, T.H.,Nordlund, P.
Fragment-based ligand design of novel potent inhibitors of tankyrases.
J.Med.Chem., 56:4497-4508, 2013

PubMed Abstract: Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding. Evolution of the fragment hit 4-methyl-1,2-dihydroquinolin-2-one (2) along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2-fluorophenyl)-4-methylquinolin-2(1H)-one (11) reveals that the nonplanar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other poly(ADP-ribose) polymerase (PARP) family members. A further cycle of optimization yielded compounds with affinities and IC50 values in the low nanomolar range and with good solubility, PARP selectivity, and ligand efficiency.

PubMed: 23672613
DOI: 10.1021/jm400211f

Experimental method

X-RAY DIFFRACTION (2 Å)