Exploring the Polypharmacological Potential of PCI-27483: A Selective Inhibitor of Carbonic Anhydrases IX and XII

被引：5

作者：

D'Agostino, Ilaria ^{[1
,2
]}

Bonardi, Alessandro ^{[2
]}

Ferraroni, Marta ^{[3
]}

Gratteri, Paola ^{[2
]}

Angeli, Andrea ^{[2
]}

Supuran, Claudiu T. ^{[2
]}

机构：

[1] Univ Pisa, Dept Pharm, I-56126 Pisa, Italy

[2] Univ Florence, NEUROFARBA Dept, Sez Sci Farmaceut, I-50019 Florence, Italy

[3] Univ Florence, Dept Chem Ugo Schiff, I-50019 Florence, Italy

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2024年 / 15卷 / 11期

关键词：

carbonic anhydrase; metalloenzyme; PCI-27483; sulfonamide; cancer; drug repositioning;

D O I：

10.1021/acsmedchemlett.4c00443

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

PCI-27483, originally developed as a potent and selective inhibitor of the serine protease Factor VIIa (FVIIa) in complex with tissue factor (TF), has demonstrated significant promise in cancer therapy. In addition to its primary mechanism of action, the presence of a sulfonamide moiety in the PCI-27483 structure suggests further activities through the inhibition of carbonic anhydrases (CAs), particularly the tumor-associated human (h)CA isoforms hCA IX and XII. This study investigates the inhibitory activity of PCI-27483 against the complete panel of active hCAs, highlighting its polypharmacological potential in cancer treatment. X-ray crystallography and molecular docking studies elucidated the structural features underlying its selective inhibitory activity toward hCA IX and XII, offering insights into its dual-targeting pathway.

引用

页码：2042 / 2045

页数：4

共 20 条

[1] The dopamine D2 receptors antagonist Veralipride inhibits carbonic anhydrases: solution and crystallographic insights on human isoforms [J].

Angeli, Andrea ;

Ferraroni, Marta ;

Capasso, Clemente ;

Supuran, Claudiu T. .

CHEMISTRY-AN ASIAN JOURNAL, 2024, 19 (08)

[2] Novel Carbonic Anhydrase Inhibitors with Dual-Tail Core Sulfonamide Show Potent and Lasting Effects for Glaucoma Therapy [J].

Angeli, Andrea ;

Chelli, Irene ;

Lucarini, Laura ;

Sgambellone, Silvia ;

Marri, Silvia ;

Villano, Serafina ;

Ferraroni, Marta ;

De Luca, Viviana ;

Capasso, Clemente ;

Carta, Fabrizio ;

Supuran, Claudiu T. .

JOURNAL OF MEDICINAL CHEMISTRY, 2024, 67 (04) :3066-3089

[3] First-in-Class Dual Hybrid Carbonic Anhydrase Inhibitors and Transient Receptor Potential Vanilloid 1 Agonists Revert Oxaliplatin- Induced Neuropathy [J].

Angeli, Andrea ;

Micheli, Laura ;

Carta, Fabrizio ;

Ferraroni, Marta ;

Pirali, Tracey ;

Carvajal, Asia Fernandez ;

Montiel, Antonio Ferrer ;

Mannelli, Lorenzo Di Cesare ;

Ghelardini, Carla ;

Supuran, Claudiu T. .

JOURNAL OF MEDICINAL CHEMISTRY, 2023, 66 (02) :1616-1633

[4]

[Anonymous], STUD SLC 0111 GEMC M

[5] Multidrug Resistance in Cancer: Understanding Molecular Mechanisms, Immunoprevention and Therapeutic Approaches [J].

Bin Emran, Talha ;

Shahriar, Asif ;

Mahmud, Aar Rafi ;

Rahman, Tanjilur ;

Abir, Mehedy Hasan ;

Siddiquee, Mohd. Faijanur-Rob ;

Ahmed, Hossain ;

Rahman, Nova ;

Nainu, Firzan ;

Wahyudin, Elly ;

Mitra, Saikat ;

Dhama, Kuldeep ;

Habiballah, Mahmoud M. ;

Haque, Shafiul ;

Islam, Ariful ;

Hassan, Mohammad Mahmudul .

FRONTIERS IN ONCOLOGY, 2022, 12

[6] Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J].

Bray, Freddie ;

Laversanne, Mathieu ;

Sung, Hyuna ;

Ferlay, Jacques ;

Siegel, Rebecca L. ;

Soerjomataram, Isabelle ;

Jemal, Ahmedin .

CA-A CANCER JOURNAL FOR CLINICIANS, 2024, 74 (03) :229-263

[7] Targeting Hypoxia-Induced Carbonic Anhydrase IX Enhances Immune-Checkpoint Blockade Locally and Systemically [J].

Chafe, Shawn C. ;

McDonald, Paul C. ;

Saberi, Saeed ;

Nemirovsky, Oksana ;

Venkateswaran, Geetha ;

Burugu, Samantha ;

Gao, Dongxia ;

Delaidelli, Alberto ;

Kyle, Alastair H. ;

Baker, Jennifer H. E. ;

Gillespie, Jordan A. ;

Bashashati, Ali ;

Minchinton, Andrew, I ;

Zhou, Youwen ;

Shah, Sohrab P. ;

Dedhar, Shoukat .

CANCER IMMUNOLOGY RESEARCH, 2019, 7 (07) :1064-1078

[8]

Hembrough TA, 2003, CANCER RES, V63, P2997

[9]

KHALIFAH RG, 1971, J BIOL CHEM, V246, P2561

[10] Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside [J].

McDonald, Paul C. ;

Chafe, Shawn C. ;

Supuran, Claudiu T. ;

Dedhar, Shoukat .

CANCERS, 2022, 14 (14)

← 1 2 →