4Q0L

Crystal structure of catalytic domain of human carbonic anhydrase isozyme XII with inhibitor

4Q0L の概要

• エントリーDOI: 10.2210/pdb4q0l/pdb
• 関連するPDBエントリー: 4PYX 4PYY 4PZH 4Q06 4Q07 4Q08 4Q09
• 分子名称: Carbonic anhydrase 12, ZINC ION, 3-(cyclooctylamino)-2,5,6-trifluoro-4-[(2-hydroxyethyl)sulfonyl]benzenesulfonamide, ... (4 entities in total)
• 機能のキーワード: drug design, carbonic anhydrase, benzenesulfonamide, metal-binding, lyase-lyase inhibitor comple, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: O43570
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 121708.86

構造登録者

Smirnov, A.,Manakova, E.,Grazulis, S. (登録日: 2014-04-02, 公開日: 2015-01-28, 最終更新日: 2023-09-20)

主引用文献

Dudutiene, V.,Matuliene, J.,Smirnov, A.,Timm, D.D.,Zubriene, A.,Baranauskiene, L.,Morkunaite, V.,Smirnoviene, J.,Michailoviene, V.,Juozapaitiene, V.,Mickeviciute, A.,Kazokaite, J.,Baksyte, S.,Kasiliauskaite, A.,Jachno, J.,Revuckiene, J.,Kisonaite, M.,Pilipuityte, V.,Ivanauskaite, E.,Milinaviciute, G.,Smirnovas, V.,Petrikaite, V.,Kairys, V.,Petrauskas, V.,Norvaisas, P.,Linge, D.,Gibieza, P.,Capkauskaite, E.,Zaksauskas, A.,Kazlauskas, E.,Manakova, E.,Grazulis, S.,Ladbury, J.E.,Matulis, D.
Discovery and characterization of novel selective inhibitors of carbonic anhydrase IX.
J.Med.Chem., 57:9435-9446, 2014

PubMed Abstract: Human carbonic anhydrase IX (CA IX) is highly expressed in tumor tissues, and its selective inhibition provides a potential target for the treatment of numerous cancers. Development of potent, highly selective inhibitors against this target remains an unmet need in anticancer therapeutics. A series of fluorinated benzenesulfonamides with substituents on the benzene ring was designed and synthesized. Several of these exhibited a highly potent and selective inhibition profile against CA IX. Three fluorine atoms significantly increased the affinity by withdrawing electrons and lowering the pKa of the benzenesulfonamide group. The bulky ortho substituents, such as cyclooctyl or even cyclododecyl groups, fit into the hydrophobic pocket in the active site of CA IX but not CA II, as shown by the compound's co-crystal structure with chimeric CA IX. The strongest inhibitor of recombinant human CA IX's catalytic domain in human cells achieved an affinity of 50 pM. However, the high affinity diminished the selectivity. The most selective compound for CA IX exhibited 10 nM affinity. The compound that showed the best balance between affinity and selectivity bound with 1 nM affinity. The inhibitors described in this work provide the basis for novel anticancer therapeutics targeting CA IX.

PubMed: 25358084
DOI: 10.1021/jm501003k

実験手法

X-RAY DIFFRACTION (2 Å)