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Expert Review of Anticancer Therapy Apr 2007P-glycoprotein actively transports structurally unrelated compounds out of cells, conferring the multidrug resistance phenotype in cancer. Tariquidar is a potent,... (Review)
Review
P-glycoprotein actively transports structurally unrelated compounds out of cells, conferring the multidrug resistance phenotype in cancer. Tariquidar is a potent, specific, noncompetitive inhibitor of P-glycoprotein. Tariquidar inhibits the ATPase activity of P-glycoprotein, suggesting that the modulating effect is derived from the inhibition of substrate binding, inhibition of ATP hydrolysis or both. In clinical trials, tariquidar is tolerable and does not have significant pharmacokinetic interaction with chemotherapy. In patients, inhibition of P-glycoprotein has been demonstrated for 48 h after a single dose of tariquidar. Studies to assess a possible increase in toxicity of chemotherapy and the impact of P-glycoprotein inhibition on tumor response and patient outcome are ongoing. Tariquidar can be considered an ideal agent for testing the role of P-glycoprotein inhibition in cancer.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Protein Transport; Quinolines
PubMed: 17428165
DOI: 10.1586/14737140.7.4.447 -
European Journal of Medicinal Chemistry Apr 2020Tariquidar derivatives have been described as potent and selective ABCG2 inhibitors. However, their susceptibility to hydrolysis limits their applicability. The current...
Tariquidar derivatives have been described as potent and selective ABCG2 inhibitors. However, their susceptibility to hydrolysis limits their applicability. The current study comprises the synthesis and characterization of novel tariquidar-related inhibitors, obtained by bioisosteric replacement of the labile moieties in our previous tariquidar analog UR-ME22-1 (9). CuAAC ("click" reaction) gave convenient access to a triazole core as a substitute for the labile amide group and the labile ester moiety was replaced by different acyl groups in a Sugasawa reaction. A stability assay proved the enhancement of the stability in blood plasma. Compounds UR-MB108 (57) and UR-MB136 (59) inhibited ABCG2 in a Hoechst 33342 transport assay with an IC value of about 80 nM and belong to the most potent ABCG2 inhibitors described so far. Compound 57 was highly selective, whereas its PEGylated analog 59 showed some potency at ABCB1. Both 57 and 59 produced an ABCG2 ATPase-depressing effect which is in agreement with our precedent cryo-EM study identifying 59 as an ATPase inhibitor that exerts its effect via locking the inward-facing conformation. Thermostabilization of ABCG2 by 57 and 59 can be taken as a hint to comparable binding to ABCG2. As reference substances, compounds 57 and 59 allow additional mechanistic studies on ABCG2 inhibition. Due to their stability in blood plasma, they are also applicable in vivo. The highly specific inhibitor 57 is suited for PET labeling, helping to further elucidate the (patho)physiological role of ABCG2, e.g. at the BBB.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Dose-Response Relationship, Drug; Humans; KB Cells; MCF-7 Cells; Molecular Structure; Neoplasm Proteins; Quinolines; Structure-Activity Relationship; Triazoles; Tumor Cells, Cultured
PubMed: 32105979
DOI: 10.1016/j.ejmech.2020.112133 -
Molecular Cancer Therapeutics Jul 2022Antibody-drug conjugates (ADC) represent a fast-growing drug class in oncology. However, ADCs are associated with resistance, and therapies able to overcome it are of...
Antibody-drug conjugates (ADC) represent a fast-growing drug class in oncology. However, ADCs are associated with resistance, and therapies able to overcome it are of utmost importance. Recently, enfortumab vedotin-ejfv (EV) was approved in nectin-4+ metastatic urothelial cancer. We previously described PVRL4/nectin-4 as a new therapeutic target in breast cancer and produced an efficient EV-like ADC comprising a human anti-nectin-4 mAb conjugated to monomethyl auristatin-E (MMAE) named N41mab-vcMMAE. To study the consequence of the long-term treatment with this ADC, we developed a preclinical breast cancer model in mice, and report a mechanism of resistance to N41mab-vcMMAE after 9-month treatment and a way to reverse it. RNA-sequencing pointed to an upregulation in resistant tumors of ABCB1 expression, encoding the multidrug resistance protein MDR-1/P-glycoprotein (P-gp), associated with focal gene amplification and high protein expression. Sensitivity to N41mab-vcMMAE of the resistant model was restored in vitro by P-gp pharmacologic inhibitors, like tariquidar. P-gp is expressed in a variety of normal tissues. By delivering the drug to the tumor more specifically than classical chemotherapy, we hypothesized that the combined use of ADC with P-gp inhibitors might reverse resistance in vivo without toxicity. Indeed, we showed that the tariquidar/N41mab-vcMMAE combination was well tolerated and induced a rapid regression of ADC-resistant tumors in mice. In contrast, the tariquidar/docetaxel combination was toxic and poorly efficient. These results show that ABC transporter inhibitors can be safely used with ADC to reverse ADC-induced resistance and open new opportunities in the fight against multidrug resistance.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Transitional Cell; Cell Adhesion Molecules; Cell Line, Tumor; Female; Humans; Immunoconjugates; Mice
PubMed: 35534238
DOI: 10.1158/1535-7163.MCT-22-0013 -
Drug Metabolism and Disposition: the... Feb 2016Since its development, tariquidar (TQR; XR9576;...
Since its development, tariquidar (TQR; XR9576; N-[2-[[4-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]carbamoyl]-4,5-dimethoxyphenyl]quinoline-3-carboxamide) has been widely regarded as one of the more potent inhibitors of P-glycoprotein (P-gp), an efflux transporter of the ATP-binding cassette (ABC) transporter family. A third-generation inhibitor, TQR exhibits high affinity for P-gp, although it is also a substrate of another ABC transporter, breast cancer resistance protein (BCRP). Recently, several studies have questioned the mechanism by which TQR interfaces with P-gp, suggesting that TQR is a substrate for P-gp instead of a noncompetitive inhibitor. We investigated TQR and its interaction with human and mouse P-gp to determine if TQR is a substrate of P-gp in vitro. To address these questions, we used multiple in vitro transporter assays, including cytotoxicity, flow cytometry, accumulation, ATPase, and transwell assays. A newly generated BCRP cell line was used as a positive control that demonstrates TQR-mediated transport. Based on our results, we conclude that TQR is a potent inhibitor of both human and mouse P-gp and shows no signs of being a substrate at the concentrations tested. These in vitro data further support our position that the in vivo uptake of [(11)C]TQR into the brain can be explained by its high-affinity binding to P-gp and by it being a substrate of BCRP, followed by amplification of the brain signal by ionic trapping in acidic lysosomes.
Topics: 3T3 Cells; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Adenosine Triphosphatases; Animals; Brain; Cell Line; Cell Line, Transformed; Humans; KB Cells; MCF-7 Cells; Mice; Quinolines
PubMed: 26658428
DOI: 10.1124/dmd.115.067785 -
The AAPS Journal Sep 2009The review summarizes the most recent achievements in structure-activity relationship (SAR) studies of tariquidar and its analogs. Tariquidar is one of the most... (Review)
Review
The review summarizes the most recent achievements in structure-activity relationship (SAR) studies of tariquidar and its analogs. Tariquidar is one of the most promising representatives of the third generation of multidrug resistance (MDR) modulators created so far. This fact determines the strong interest of different research groups in the development of tariquidar-like structures as selective inhibitors of MDR transporters in resistant human cancer cells. After the discovery of tariquidar, a number of analogs have been synthesized and pharmacologically tested, thus supplying good data for comprehensive analyses of their structure-activity relationships. In the review, the structural and pharmacological data of newly synthesized tariquidar-like compounds are first presented. Next, the main achievements in the SAR studies are described focusing on two main transport proteins: P-glycoprotein and breast cancer resistance protein. The reported results are discussed from the point of view of their significance and importance for future directions in the rational design of effective MDR modulators.
Topics: Drug Resistance, Multiple; Models, Molecular; Quinolines; Structure-Activity Relationship
PubMed: 19504188
DOI: 10.1208/s12248-009-9118-z -
ACS Medicinal Chemistry Letters Aug 2018ABC transporters, including ABCG2, play a vital role in defending the human body against the vast range of xenobiotics. Even though this is beneficial for human health,...
ABC transporters, including ABCG2, play a vital role in defending the human body against the vast range of xenobiotics. Even though this is beneficial for human health, these protein transporters have been implicated in the emerging resistance of cancer cells to a variety of structurally and functionally diverse anticancer drugs. In order to investigate their role in resistance, potent and selective ABCG2 modulators have been described in the literature. A leading class of modulators are the tariquidar analogues; however, their susceptibility to hydrolysis limits their applicable use. To overcome this, we synthesized a novel series of chalcone- and ketone-based compounds inspired by reported tariquidar analogues. Compounds were characterized and evaluated for their ABCG2 modulatory activity and ABC transporter selectivity. When compared to transporters ABCB1 and ABCC1, the chalcone-based compounds exhibited selectivity for ABCG2, while the ketone-based compounds showed only a slight preference for ABCG2. From the former series, chalcone (UR-DP48) displayed similar activity to the reference fumitremorgin C, both producing comparable maximal effects. The compound exhibited marked antiproliferative activity, while cytotoxicity was less pronounced for the most active compound from the ketone series. Chalcone-containing tariquidar analogues are promising modulators to aid in functional investigations of ABCG2 transporters.
PubMed: 30128080
DOI: 10.1021/acsmedchemlett.8b00289 -
Cells Mar 2021Zebrafish has emerged as a powerful model in studies dealing with pigment development and pathobiology of pigment diseases. Due to its conserved pigment pattern with...
Zebrafish has emerged as a powerful model in studies dealing with pigment development and pathobiology of pigment diseases. Due to its conserved pigment pattern with established genetic background, the zebrafish is used for screening of active compounds influencing melanophore, iridophore, and xanthophore development and differentiation. In our study, zebrafish embryos and larvae were used to investigate the influence of third-generation noncompetitive P-glycoprotein inhibitor, tariquidar (TQR), on pigmentation, including phenotype effects and changes in gene expression of chosen chromatophore differentiation markers. Five-day exposure to increasing TQR concentrations (1 µM, 10 µM, and 50 µM) resulted in a dose-dependent augmentation of the area covered with melanophores but a reduction in the area covered by iridophores. The observations were performed in three distinct regions-the eye, dorsal head, and tail. Moreover, TQR enhanced melanophore renewal after depigmentation caused by 0.2 mM 1-phenyl-2-thiourea (PTU) treatment. qPCR analysis performed in 56-h post-fertilization (hpf) embryos demonstrated differential expression patterns of genes related to pigment development and differentiation. The most substantial findings include those indicating that TQR had no significant influence on leukocyte tyrosine kinase, GTP cyclohydrolase 2, tyrosinase-related protein 1, and forkhead box D3, however, markedly upregulated tyrosinase, dopachrome tautomerase and melanocyte inducing transcription factor, and downregulated purine nucleoside phosphorylase 4a. The present study suggests that TQR is an agent with multidirectional properties toward pigment cell formation and distribution in the zebrafish larvae and therefore points to the involvement of P-glycoprotein in this process.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Cell Differentiation; Gene Expression Profiling; Gene Expression Regulation; Gene Expression Regulation, Developmental; Larva; Melanins; Melanophores; Pigmentation; Quinolines; RNA, Messenger; Zebrafish; Zebrafish Proteins
PubMed: 33804686
DOI: 10.3390/cells10030690 -
Journal of Separation Science Jul 2022A liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of vincristine and tariquidar in 10 μL of mouse...
Quantification of vincristine and tariquidar by liquid chromatography-tandem mass spectrometry in mouse whole blood using volumetric absorptive microsampling for pharmacokinetic applications.
A liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of vincristine and tariquidar in 10 μL of mouse whole blood using volumetric absorptive microsampling devices. Samples were extracted from the devices and quantified against calibrators prepared in a human blood plasma matrix. Separation of vincristine and tariquidar was achieved using a Shimpack XR ODS III C18 stationary phase and H O and methanol mobile phase solvents containing 0.1% formic acid, running a gradient elution at a flow rate of 0.2 mL/min over 6.0 min. The method was linear up to 1200 ng/mL (R > 0.99 for both analytes), with calibrator accuracy within ± 15% of the nominal concentrations and analyte coefficient of variance <15% for both vincristine and tariquidar. Pharmacokinetic assessment of both analytes was successfully applied in mice as both single-agent therapy and combination therapy over a 24-h period, and a 2.3-fold increase in vincristine drug exposure was observed in combination with tariquidar. This study validates the use of this approach for longitudinal analysis of drug exposure in animal studies.
Topics: Animals; Chromatography, High Pressure Liquid; Chromatography, Liquid; Humans; Mice; Quinolines; Reproducibility of Results; Tandem Mass Spectrometry; Vincristine
PubMed: 35567751
DOI: 10.1002/jssc.202101013 -
Nanoscale Oct 2021As an efflux pump, P-glycoproteins (P-gps) are over-expressed in many cancer cell types to confer them with multi-drug resistance. Many studies have focused on...
As an efflux pump, P-glycoproteins (P-gps) are over-expressed in many cancer cell types to confer them with multi-drug resistance. Many studies have focused on elucidating their molecular structure or protein expression; however, the relationship between the molecular assembly and dysfunction remains unclear. Super-resolution microscope is an excellent imaging tool to reveal the molecular biological details, but its high-quality imaging often suffers from the labeling method currently available. In this work, by exploiting its specificity and small size, tariquidar (specific inhibitor of P-gp) was modified by TAMRA to form a small chemical probe of P-gp. By direct stochastic optical reconstruction microscopic (dSTORM) imaging, tariquidar-TAMRA was first revealed to possess a higher labeling superiority and high binding specificity. Then, with the application of tariquidar-TAMRA labeling, we found that P-gps accumulate into larger and denser clusters on cancer cells and drug-resistant cells than on normal cells and drug-sensitive cells, indicating that P-gps can facilitate the pumping efficiency by aggregating together to form functional platforms. Moreover, these specific distribution patterns might serve as potential biomarkers for tumor and drug therapy screening.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Resistance, Multiple; Quinolines
PubMed: 34617531
DOI: 10.1039/d1nr03980f -
Frontiers in Molecular Biosciences 2024The human multidrug transporter P-glycoprotein (P-gp) is physiologically essential and of key relevance to biomedicine. Recent structural studies have shed light on the...
The human multidrug transporter P-glycoprotein (P-gp) is physiologically essential and of key relevance to biomedicine. Recent structural studies have shed light on the mode of inhibition of the third-generation inhibitors for human P-gp, but the molecular mechanism by which these inhibitors enter the transmembrane sites remains poorly understood. In this study, we utilized all-atom molecular dynamics (MD) simulations to characterize human P-gp dynamics under a potent inhibitor, tariquidar, bound condition, as well as the atomic-level binding pathways in an explicit membrane/water environment. Extensive unbiased simulations show that human P-gp remains relatively stable in tariquidar-free and bound states, while exhibiting a high dynamic binding mode at either the drug-binding pocket or the regulatory site. Free energy estimations by partial nudged elastic band (PNEB) simulations and Molecular Mechanics Generalized Born Surface Area (MM/GBSA) method identify two energetically favorable binding pathways originating from the cytoplasmic gate with an extended tariquidar conformation. Interestingly, free tariquidar in the lipid membrane predominantly adopts extended conformations similar to those observed at the regulatory site. These results suggest that membrane lipids may preconfigure tariquidar into an active ligand conformation for efficient binding to the regulatory site. However, due to its conformational plasticity, tariquidar ultimately moves toward the drug-binding pocket in both pathways, explaining how it acts as a substrate at low concentrations. Our molecular findings propose a membrane-assisted mechanism for the access and binding of the third-generation inhibitors to the binding sites of human P-gp, and offer deeper insights into the molecule design of more potent inhibitors against P-gp-mediated drug resistance.
PubMed: 38560519
DOI: 10.3389/fmolb.2024.1364494