4IUE

Tankyrase in complex with 7-(2-fluorophenyl)-4-methyl-1,2-dihydroquinolin-2-one

4IUE の概要

• エントリーDOI: 10.2210/pdb4iue/pdb
• 関連するPDBエントリー: 3W51
• 分子名称: Tankyrase-2, ZINC ION, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: ribosylations, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q9H2K2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24504.00

構造登録者

Jansson, A.E.,Larsson, E.A.,Nordlund, P.L. (登録日: 2013-01-21, 公開日: 2013-06-26, 最終更新日: 2023-11-08)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.38 Å)