The acidic tumor microenvironment drives a stem-like phenotype in melanoma cells DOI Creative Commons
Elena Andreucci, Silvia Peppicelli, Jessica Ruzzolini

et al.

Journal of Molecular Medicine, Journal Year: 2020, Volume and Issue: 98(10), P. 1431 - 1446

Published: Aug. 15, 2020

Abstract Acidosis characterizes the microenvironment of most solid tumors and is considered a new hallmark cancer. It mainly caused by both “aerobic” “anaerobic” glycolysis differently adapted cancer cells, with final product lactic acid being responsible extracellular acidification. Many evidences underline role acidosis in tumor progression. Among different findings, we demonstrated that acidosis-exposed cells are characterized an epithelial-to-mesenchymal transition phenotype high invasive ability, resistance to apoptosis, anchorage-independent growth, drug therapy. Acidic melanoma over-express SOX2, which crucial for maintenance their oxidative metabolism, carbonic anhydrase IX, correlates poor prognosis patients. Considering these evidences, realized profile outlined inevitably remind us stemness profile. Therefore, wondered whether might induce acquisition stem-like properties contribute expansion stem cell sub-population. We found chronic adaptation stimulates expression stem-related markers, also providing vitro/in vivo clonogenic trans-differentiating ability. Moreover, observed acidosis-induced was reversible related EMT induction. These findings help characterize further aspect niche, contributing sustainment subpopulation. Thus, usage agents controlling acquire great importance clinic treatment aggressive tumor. Key messages • Extracellular up-regulates markers medium vitro self-renewal capacity Chronic induces trans-differentiation ability Melanoma show higher tumor-initiating potential than control promotes prostate colorectal carcinoma

Language: Английский

Exploration of 1,2,3-triazole linked benzenesulfonamide derivatives as isoform selective inhibitors of human carbonic anhydrase DOI Open Access

Chnar Kakakhan,

Cüneyt Türkeş, Özcan Güleç

et al.

Bioorganic & Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 77, P. 117111 - 117111

Published: Nov. 29, 2022

Language: Английский

Citations

82
Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside DOI Open Access
Paul C. McDonald, Shawn C. Chafe, Claudiu T. Supuran

et al.

Cancers, Journal Year: 2022, Volume and Issue: 14(14), P. 3297 - 3297

Published: July 6, 2022

Carbonic Anhydrase IX (CAIX) is a major metabolic effector of tumor hypoxia and regulates intra- extracellular pH acidosis. Significant advances have been made recently in the development therapeutic targeting CAIX. These approaches include antibody-based immunotherapy, as well use antibodies to deliver toxic radioactive payloads. In addition, large number small molecule inhibitors which inhibit enzymatic activity CAIX described. this commentary, we highlight current status strategies both pre-clinical clinical space, discuss future perspectives that leverage inhibition combination with additional targeted therapies enable effective, durable for cancer therapy.

Language: Английский

Citations

76
Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies DOI Creative Commons
Mateusz Kciuk, Adrianna Gielecińska, Somdutt Mujwar

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 1278 - 1298

Published: May 4, 2022

Carbonic anhydrases IX and CAXII (CAIX/CAXII) are transmembrane zinc metalloproteins that catalyze a very basic but crucial physiological reaction: the conversion of carbon dioxide into bicarbonate with release proton. CA, especially CAIX isoforms gained attention many researchers interested in anticancer drug design due to pivotal functions enzymes cancer cell metastasis response hypoxia, their expression restricted malignant cells. This offers an opportunity develop new targeted therapies fewer side effects. Continuous efforts led discovery series diverse compounds most abundant sulphonamide derivatives. Here we review current knowledge considering small molecule antibody-based targeting CAIX/CAXII cancer.

Language: Английский

Citations

74
Carboranes as unique pharmacophores in antitumor medicinal chemistry DOI Creative Commons
Yu Chen, Fukuan Du,

Liyao Tang

et al.

Molecular Therapy — Oncolytics, Journal Year: 2022, Volume and Issue: 24, P. 400 - 416

Published: Jan. 10, 2022

Carborane is a carbon-boron molecular cluster that can be viewed as 3D analog of benzene. It features special physical and chemical properties, thus has the potential to serve new type pharmacophore for drug design discovery. Based on relative positions two cage carbons, icosahedral closo-carboranes classified into three isomers, ortho-carborane (o-carborane, 1,2-C2B10H12), meta-carborane (m-carborane, 1,7-C2B10H12), para-carborane (p-carborane, 1,12-C2B10H12), all them deboronated generate their nido- forms. Cage compound carborane its derivatives have been demonstrated useful entities in antitumor medicinal chemistry. The applications carboranes field research mainly include boron neutron capture therapy (BNCT), BNCT/photodynamic dual sensitizers, anticancer ligands. This review summarizes progress achieved up October 2021, with particular emphasis signaling transduction pathways, structures, mechanistic considerations using carboranes.

Language: Английский

Citations

73
A simple yet multifaceted 90 years old, evergreen enzyme: Carbonic anhydrase, its inhibition and activation DOI
Claudiu T. Supuran

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2023, Volume and Issue: 93, P. 129411 - 129411

Published: July 27, 2023

Language: Английский

Citations

63
Exploring the multiple binding modes of inhibitors to carbonic anhydrases for novel drug discovery DOI
Claudiu T. Supuran

Expert Opinion on Drug Discovery, Journal Year: 2020, Volume and Issue: 15(6), P. 671 - 686

Published: March 25, 2020

Introduction The spacious active site cavity of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) shows a great versatility for variety binding modes modulators activity, inhibitors, and activators, some which are clinically used drugs.Areas covered There at least four well-documented CA inhibition mechanisms same number inhibitors (CAIs), one superposes with activators (CAAs). They include (i) coordination to catalytic metal ion; (ii) anchoring water molecule coordinated (iii) occlusion entrance; (iv) outside site. A large chemical classes CAIs show these explored in detail by kinetic, crystallographic, other techniques. tail approach was applied all them allowed many highly isoform-selective inhibitors. This is subject our review.Expert opinion All regions CAs accommodate bind, reflected very different profiles such compounds possibility design drugs effective action new applications, as management hypoxic tumors, neuropathic pain, cerebral ischemia, arthritis, degenerative disorders.

Language: Английский

Citations

115
Reconsidering anion inhibitors in the general context of drug design studies of modulators of activity of the classical enzyme carbonic anhydrase DOI Creative Commons
Alessio Nocentini, Andrea Angeli, Fabrizio Carta

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 36(1), P. 561 - 580

Published: Jan. 1, 2021

Inorganic anions inhibit the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) generally by coordinating to active site metal ion. Cyanate was reported as a non-coordinating CA inhibitor but those erroneous results were subsequently corrected another group. We review anion inhibitors (CAIs) in more general context of drug design studies and discovery large number classes inhibition mechanisms, including zinc binders (sulphonamides isosteres, dithiocabamates thiols, selenols, benzoxaboroles, ninhydrins, etc.); anchoring zinc-coordinated water molecule (phenols, polyamines, sulfocoumarins, thioxocoumarins, catechols); CAIs occluding entrance (coumarins derivatives, lacosamide), well compounds that bind outside site. All these new chemotypes integrated with procedure for obtaining isoform-selective (the tail approach) has resulted, through guidance rigorous X-ray crystallography experiments, development highly selective all human isoforms many pharmacological applications.

Language: Английский

Citations

104
Advances in the discovery of exosome inhibitors in cancer DOI Creative Commons
Huarui Zhang, Jun Lü, Jin Liu

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 35(1), P. 1322 - 1330

Published: Jan. 1, 2020

Exosomes are small membrane vesicles released by most eukaryotic cells. They considered to play an essential role in cell-to-cell communication, and It is also found that they serve as functional mediators many severe diseases, including progression of various types cancers. Inhibition exosome release may slow the some cancers; thus, has been attractive target for cancer treatment. Over years, considerable efforts have made discover novel, highly potent excellently selective inhibitors. Most these inhibitors derived from synthetic compounds, which currently existed drugs potential inhibit release. In this review, we briefly discussed development discovered provided guidance future

Language: Английский

Citations

103
Applications of carbonic anhydrases inhibitors in renal and central nervous system diseases DOI
Claudiu T. Supuran

Expert Opinion on Therapeutic Patents, Journal Year: 2018, Volume and Issue: 28(10), P. 713 - 721

Published: Sept. 2, 2018

Introduction: There are tissues and organs, among which kidneys the central nervous system (CNS), rich in various isoforms of metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Their role is to regulate pH, provide bicarbonate or H+ ions for electrolyte secretion possibly a metabolic one. Considering these two systems, CA inhibitors clinically used mainly as diuretics antiepileptics, but novel applications management drug-induced renal injury, sleep apnea, migraine, lowering intracranial pressure, cognitive impairment, neuropathic pain, cerebral ischemia have emerged.Areas covered: The classes used/investigational their CNS – connected diseases reviewed. A patent literature review covering period 2013–2018 presented.Expert opinion: Both many (CAIs), present also high amounts. inhibition activation has pharmacological applications, already exploited diuretic antiepileptic drugs decades. New were demonstrated last years CAIs idiopathic hypertension, ischemia, avoiding disruption blood-brain barrier, prevention/treatment activators cognition enhancement possible treatment posttraumatic shock phobias.

Language: Английский

Citations

101
Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action DOI Creative Commons
Alessandro Bonardi, Alessio Nocentini, Silvia Bua

et al.

Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 63(13), P. 7422 - 7444

Published: June 10, 2020

The "tail approach" has become a milestone in human carbonic anhydrase inhibitor (hCAI) design for various therapeutics, including antiglaucoma agents. Besides the classical hydrophobic/hydrophilic division of hCAs active site, several subpockets have been identified at middle/outer sites rim, which could be targeted to increase CAI isoform selectivity. This postulate is explored here by three-tailed benzenesulfonamide CAIs (TTI) fully exploit such amino acid differences among hCAs. In this proof-of-concept study, an extensive structure-activity relationship (SAR) study was carried out with 32 benzenesulfonamides differing tails combination that were assayed I, II, IV, and XII inhibition. A structural undertaken X-ray crystallography silico tools assess ligand/target interaction mode. most selective inhibitors against isoforms implicated glaucoma assessed rabbit model disease achieving intraocular pressure-lowering action comparable clinically used dorzolamide.

Language: Английский

Citations

95