6YPW

Crystal structure for the complex of human carbonic anhydrase II and 4-((1-(2-(hydroxymethyl)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzenesulfonamide

6YPW の概要

• エントリーDOI: 10.2210/pdb6ypw/pdb
• 分子名称: Carbonic anhydrase 2, ZINC ION, 4-[[1-[(2~{S},3~{S},5~{R})-2-(hydroxymethyl)-5-[5-methyl-2,4-bis(oxidanylidene)pyrimidin-1-yl]oxolan-3-yl]-1,2,3-triazol-4-yl]methoxy]benzenesulfonamide, ... (4 entities in total)
• 機能のキーワード: carbonic anhydrase inhibitors; azt; telomerase inhibitors; cancer; molecular hybrids; click chemistry; triazole., lyase
• 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: 29832.95

構造登録者

Angeli, A.,Ferraroni, M. (登録日: 2020-04-16, 公開日: 2021-04-28, 最終更新日: 2024-01-31)

主引用文献

Plyasova, A.A.,Berrino, E.,Khan, I.I.,Veselovsky, A.V.,Pokrovsky, V.S.,Angeli, A.,Ferraroni, M.,Supuran, C.T.,Pokrovskaya, M.V.,Alexandrova, S.S.,Gladilina, Y.A.,Sokolov, N.N.,Hilal, A.,Carta, F.,Zhdanov, D.D.
Mechanisms of the Antiproliferative and Antitumor Activity of Novel Telomerase-Carbonic Anhydrase Dual-Hybrid Inhibitors.
J.Med.Chem., 64:11432-11444, 2021

PubMed Abstract: Human (h) telomerase (TL; EC 2.7.7.49) plays a key role in sustaining cancer cells by means of elongating telomeric repeats at the 3' ends of chromosomes. Since TL-inhibitor (TI) stand-alone cancer therapy has been proven to be remarkably challenging, a polypharmacological approach represents a valid alternative. Here we consider a series of compounds able to inhibit both hTL and the tumor-associated carbonic anhydrases (CAs; EC 4.2.1.1) IX and XII. Compounds and suppressed hTL activity in both cell lysates and human colon cancer cell lines, and prolonged incubation with either or resulted in telomere shortening, cell cycle arrest, replicative senescence, and apoptosis. Enzyme kinetics showed that and are mixed-type inhibitors of the binding of DNA primers and deoxynucleoside triphosphate (dNTP) to the TL catalytic subunit hTERT, which is in agreement with docking experiments. Compound showed antitumor activity in Colo-205 mouse xenografts and suppressed telomerase activity by telomere reduction.

PubMed: 34283610
DOI: 10.1021/acs.jmedchem.1c00756

実験手法

X-RAY DIFFRACTION (1.1 Å)