6VJ3

Carbonic Anhydrase II in complex with pyrimidine-based inhibitor

6VJ3 の概要

• エントリーDOI: 10.2210/pdb6vj3/pdb
• 分子名称: Carbonic anhydrase 2, ZINC ION, 2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(4-sulfamoylphenyl)acetamide, ... (5 entities in total)
• 機能のキーワード: ca ii, sulfonamide, pyrimidine, inhibitor, cancer, lyase, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29552.60

構造登録者

Lomelino, C.L.,McKenna, R. (登録日: 2020-01-14, 公開日: 2020-03-11, 最終更新日: 2023-10-11)

主引用文献

Petreni, A.,Bonardi, A.,Lomelino, C.,Osman, S.M.,ALOthman, Z.A.,Eldehna, W.M.,El-Haggar, R.,McKenna, R.,Nocentini, A.,Supuran, C.T.
Inclusion of a 5-fluorouracil moiety in nitrogenous bases derivatives as human carbonic anhydrase IX and XII inhibitors produced a targeted action against MDA-MB-231 and T47D breast cancer cells.
Eur.J.Med.Chem., 190:112112-112112, 2020

PubMed Abstract: A new series of pyrimidine derivatives as human carbonic anhydrases (CA, EC 4.2.1.1) inhibitors is here designed by including a 5-fluorouracil (5-FU) moiety, broadly used anticancer medication, in nitrogenous base modulators of the tumor-associated CAs. Most sulfonamide derivatives efficiently inhibit the target CA IX (Ks in the range 0.47-44.7 nM) and CA XII (Ks in the range 2.9-83.1 nM), while the 5-FU coumarin derivatives showed a potent and totally selective inhibitory action against the target CA IX/XII over off-target CA I/II. The X-ray solved crystal structure of CA II in adduct with a representative uracil derivative provided insights on the binding mode to the target of such pyrimidine derivatives. On the basis of potency and selectivity inhibition profiles, coumarin 12a, the sulfonamide CAIs showing the greatest II/IX specificity (4e, 6b and 6d) and the unique subnanomolar CA IX inhibitor 10a were tested in vitro for their antiproliferative action against a panel of eight cancer cell lines. The breast cancer cell lines MDA-MB-231 and T47D were the most susceptible with IC values in low to medium micromolar ranges (2.45 ± 0.07-18.86 ± 0.72 μM and 6.86 ± 0.31-40.92 ± 1.59 μM, respectively). A cell cycle analysis showed that 4e and 6d arrest T-47D cells mainly in the G2/M phase. Using an annexin V-FITC apoptosis assay, 4e and 6d were shown to induce an approximately 23.6-fold and 34.8-fold total increase in apoptosis compared to the control, corroborating the concrete potential of 5-FU CAIs for the design of new effective anticancer strategies.

PubMed: 32044580
DOI: 10.1016/j.ejmech.2020.112112

実験手法

X-RAY DIFFRACTION (1.35 Å)