Converting Potent Indeno[1,2-<i>b</i>]indole Inhibitors of Protein Kinase CK2 into Selective Inhibitors of the Breast Cancer Resistance Protein ABCG2

Gozzi, Gustavo Jabor; Bouaziz, Zouhair; Winter, Evelyn; Daflon-Yunes, Nathalia; Aichele, Dagmar; Nacereddine, Abdelhamid; Marminon, Christelle; Valdameri, Gláucio; Zeinyeh, Waël; Bollacke, Andre; Guillon, Jean; Lacoudre, Aline; Pinaud, Noël; Cadena, Sílvia Maria Suter Correia; Jose, Joachim; Borgne, Marc Le; Pietro, Attilio Di

doi:10.1021/jm500943z

Cited by 66 publications

(63 citation statements)

References 55 publications

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“…It was firstly discovered in a process involving in multidrug resistance (MDR) from doxorubicin-resistant human MCF-7 breast cancer cells [4–6], and was also reported to induce sorafenib resistance in hepatocellular carcinoma (HCC) cells [7]. Further investigation indicated that ABCG2 is over-expressed in various tumor cells [8, 9].…”

Section: Introductionmentioning

confidence: 99%

ABCG2 confers promotion in gastric cancer through modulating downstream CRKL in vitro combining with biostatistics mining

et al. 2016

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ABCG2, member of ATP-binding cassette (ABC) transporter family, is known as crucial regulator related to multi-drug resistance in human tumors and has recently been putatively studied as human carcinoma cell biomarker. While, effects of ABCG2 on human gastric cancer (GC) has not been illustrated thoroughly. In this study, by applying biostatistics mining methods, we observed that ABCG2 is frequently aberrantly expressed in GC patients through exploring dataset of GSE19826 in NCBI GEO database. Contemporary, extreme up-regulation of ABCG2 was discovered in both GC specimens and cell lines of our center, from which we observed high level of ABCG2 associated with GC clinicopathologic features and poor outcomes. Depletion of ABCG2 in MKN-45 GC cells, the cell proliferation was significantly impacted along with cell cycle arrest, and cell apoptosis was induced. Interestingly, combined with data mining of NCBI database, CRKL, a pivotal GC promoter, presents a significant positive correlation with ABCG2. And the expression of CRKL in GC cells was obviously affected through ABCG2 depletion. Simultaneously, over-expression of CRKL in MKN-45 cells significantly rescued most of the phenotypes induced by ABCG2 depletion. Thus, we suggest that ABCG2 is a potential biomarker and target upstream CRKL, which could be further studied for GC diagnosis and therapeutic treatment

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Section: Introductionmentioning

confidence: 99%

ABCG2 confers promotion in gastric cancer through modulating downstream CRKL in vitro combining with biostatistics mining

et al. 2016

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“…The synthesis procedure, as well as the analytical data, are given in the supporting information. In contrast, the following ten compounds used for the training and test sets, namely 4e, 4f, 4g, 4v, 4x, 4y, 5d, 5j, 5k, and 6g, which have been published before [16,17,35]. The inhibitory activity of all used indeno [1,2-b]indoles was tested on recombinant human CK2 and the inhibition results are shown in Tables 1 and 2.…”

Section: Resultsmentioning

confidence: 99%

“…All indeno[1,2-b]indole derivatives 1-30 used in this study were synthesized by us. The procedures for the synthesis of indeno [1,2-b]indoles have already been described for compounds 4e [35], 4f [35], 4g [17], 4v [35], 4x [16], 4y [16], 5d [17], 5j [16], 5k [16], and 6g [16]. For the compounds 4d, 4h-j, 4p-s, 4w, 5a, 5c, 5f, 5h, 5g, and 6a-f, the chemistry is described in the Supporting Information (Files S1 and S2).…”

Section: Chemistrymentioning

confidence: 99%

QSAR Model of Indeno[1,2-b]indole Derivatives and Identification of N-isopentyl-2-methyl-4,9-dioxo-4,9-Dihydronaphtho[2,3-b]furan-3-carboxamide as a Potent CK2 Inhibitor

et al. 2019

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Casein kinase II (CK2) is an intensively studied enzyme, involved in different diseases, cancer in particular. Different scaffolds were used to develop inhibitors of this enzyme. Here, we report on the synthesis and biological evaluation of twenty phenolic, ketonic, and para-quinonic indeno[1,2-b]indole derivatives as CK2 inhibitors. The most active compounds were 5-isopropyl-1-methyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione 4h and 1,3-dibromo-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione 4w with identical IC50 values of 0.11 µM. Furthermore, the development of a QSAR model based on the structure of indeno[1,2-b]indoles was performed. This model was used to predict the activity of 25 compounds with naphtho[2,3-b]furan-4,9-dione derivatives, which were previously predicted as CK2 inhibitors via a molecular modeling approach. The activities of four naphtho[2,3-b]furan-4,9-dione derivatives were determined in vitro and one of them (N-isopentyl-2-methyl-4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-3-carboxamide) turned out to inhibit CK2 with an IC50 value of 2.33 µM. All four candidates were able to reduce the cell viability by more than 60% after 24 h of incubation using 10 µM.

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“…Table 1. Structures of the ketonic indeno [1,2-b]indoles and their IC50 values towards CK2, which were used for the training and test sets, data from Alchab et al [9] and Gozzi et al [13]. MOE software (Chemical Computing Group, Montreal, Canada) package was used to perform this study [21].…”

Section: Resultsmentioning

confidence: 99%

<strong>Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining</strong>

Haidar

Bouaziz

Marminon

et al. 2017

Proceedings of 3rd International Electronic Conference on Medicinal Chemistry

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Abstract:Casein kinase 2 is a ubiquitous kinase protein emerging as a target for the treatment of cancer. Several active CK2 inhibitors have been developed in the last few years; most of them have ATP-competitive type of inhibition. Indeno [1,2-b]indoles present a class of natural and synthetic compounds; many of them have different bioactivity. Here we report on the development of a ligand-based pharmacophore on the basis of different active Indeno[1,2-b]indoles (training set), the pharmacophore model was challenged against small library of Indeno[1,2-b]indoles (test set), the study was performed using MOE software. Our model demonstrates good performance in the test set, 85% of the medium or high inhibitory activity compounds were identified, while only 17% of the low or no inhibitory activity compounds were misclassified. Several structures were suggested as possible active CK2 inhibitors by using this model as a base for search in the ZINC database among them was bikaverin which was then further studied.

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Converting Potent Indeno[1,2-b]indole Inhibitors of Protein Kinase CK2 into Selective Inhibitors of the Breast Cancer Resistance Protein ABCG2

Cited by 66 publications

References 55 publications

ABCG2 confers promotion in gastric cancer through modulating downstream CRKL in vitro combining with biostatistics mining

ABCG2 confers promotion in gastric cancer through modulating downstream CRKL in vitro combining with biostatistics mining

QSAR Model of Indeno[1,2-b]indole Derivatives and Identification of N-isopentyl-2-methyl-4,9-dioxo-4,9-Dihydronaphtho[2,3-b]furan-3-carboxamide as a Potent CK2 Inhibitor

<strong>Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining</strong>

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