TY  - JOUR
AU  - Jovanović, Mirna
AU  - Dragoj, Miodrag
AU  - Zhukovsky, Daniil
AU  - Dar’in, Dmitry
AU  - Krasavin, Mikhail
AU  - Pešić, Milica
AU  - Podolski-Renić, Ana
PY  - 2020
UR  - https://www.frontiersin.org/article/10.3389/fmolb.2020.586146/full
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3944
AB  - Currently available glioblastoma (GBM) treatment remains ineffective, with relapse after initial response and low survival rate of GBM patients. Reasons behind limited capacities for GBM treatment are high tumor heterogeneity, invasiveness and occurrence of drug resistance. Therefore, developing novel therapeutic strategies is of utmost importance. Thioredoxin reductase (TrxR) is a novel, promising target due to its overexpression in many cancer types and important role in cancer progression. Previous research on Ugi-type Michael acceptors– inhibitors of TrxR, showed desirable anticancer properties, with significant selectivity towards cancer cells. Herein, two TrxR inhibitors, 5 and 6 underwent in depth study on multidrug resistant (MDR) glioma cell lines. Besides antioxidative effect, 5 and 6 induced cell death, decreased cell proliferation, suppressed invasion and migration of glioma cells. Both compounds showed a synergistic effect in combination with temozolomide (TMZ), a first line chemotherapeutic for GBM treatment. Moreover, 5 and 6 affected the activity of P-glycoprotein extrusion pump that could be found on cancer cells and in blood-brain barrier (BBB), thus showing potential for suppressing MDR phenotype in cancer cells and evading BBB. In conclusion, investigated TrxR inhibitors are effective anticancer compounds, acting through inhibition of thioredoxin system and perturbation of antioxidative defense systems of glioma cells. They are suitable for combining with other chemotherapeutics, able to surpass the BBB and overcome MDR. Thus our findings suggest further exploration of Ugi-type Michael acceptors-TrxR inhibitors’ potential as adjuvant therapy for GBM treatment.
PB  - Frontiers Media SA
T2  - Frontiers in Molecular Biosciences
T1  - Novel TrxR1 Inhibitors Show Potential for Glioma Treatment by Suppressing the Invasion and Sensitizing Glioma Cells to Chemotherapy
VL  - 7
DO  - 10.3389/fmolb.2020.586146
SP  - 281
ER  - 

@article{
author = "Jovanović, Mirna and Dragoj, Miodrag and Zhukovsky, Daniil and Dar’in, Dmitry and Krasavin, Mikhail and Pešić, Milica and Podolski-Renić, Ana",
year = "2020",
abstract = "Currently available glioblastoma (GBM) treatment remains ineffective, with relapse after initial response and low survival rate of GBM patients. Reasons behind limited capacities for GBM treatment are high tumor heterogeneity, invasiveness and occurrence of drug resistance. Therefore, developing novel therapeutic strategies is of utmost importance. Thioredoxin reductase (TrxR) is a novel, promising target due to its overexpression in many cancer types and important role in cancer progression. Previous research on Ugi-type Michael acceptors– inhibitors of TrxR, showed desirable anticancer properties, with significant selectivity towards cancer cells. Herein, two TrxR inhibitors, 5 and 6 underwent in depth study on multidrug resistant (MDR) glioma cell lines. Besides antioxidative effect, 5 and 6 induced cell death, decreased cell proliferation, suppressed invasion and migration of glioma cells. Both compounds showed a synergistic effect in combination with temozolomide (TMZ), a first line chemotherapeutic for GBM treatment. Moreover, 5 and 6 affected the activity of P-glycoprotein extrusion pump that could be found on cancer cells and in blood-brain barrier (BBB), thus showing potential for suppressing MDR phenotype in cancer cells and evading BBB. In conclusion, investigated TrxR inhibitors are effective anticancer compounds, acting through inhibition of thioredoxin system and perturbation of antioxidative defense systems of glioma cells. They are suitable for combining with other chemotherapeutics, able to surpass the BBB and overcome MDR. Thus our findings suggest further exploration of Ugi-type Michael acceptors-TrxR inhibitors’ potential as adjuvant therapy for GBM treatment.",
publisher = "Frontiers Media SA",
journal = "Frontiers in Molecular Biosciences",
title = "Novel TrxR1 Inhibitors Show Potential for Glioma Treatment by Suppressing the Invasion and Sensitizing Glioma Cells to Chemotherapy",
volume = "7",
doi = "10.3389/fmolb.2020.586146",
pages = "281"
}

Jovanović, M., Dragoj, M., Zhukovsky, D., Dar’in, D., Krasavin, M., Pešić, M.,& Podolski-Renić, A.. (2020). Novel TrxR1 Inhibitors Show Potential for Glioma Treatment by Suppressing the Invasion and Sensitizing Glioma Cells to Chemotherapy. in Frontiers in Molecular Biosciences
Frontiers Media SA., 7, 281.
https://doi.org/10.3389/fmolb.2020.586146

Jovanović M, Dragoj M, Zhukovsky D, Dar’in D, Krasavin M, Pešić M, Podolski-Renić A. Novel TrxR1 Inhibitors Show Potential for Glioma Treatment by Suppressing the Invasion and Sensitizing Glioma Cells to Chemotherapy. in Frontiers in Molecular Biosciences. 2020;7:281.
doi:10.3389/fmolb.2020.586146 .

Jovanović, Mirna, Dragoj, Miodrag, Zhukovsky, Daniil, Dar’in, Dmitry, Krasavin, Mikhail, Pešić, Milica, Podolski-Renić, Ana, "Novel TrxR1 Inhibitors Show Potential for Glioma Treatment by Suppressing the Invasion and Sensitizing Glioma Cells to Chemotherapy" in Frontiers in Molecular Biosciences, 7 (2020):281,
https://doi.org/10.3389/fmolb.2020.586146 . .

TY  - JOUR
AU  - Jovanović, Mirna
AU  - Zhukovsky, Daniil
AU  - Podolski-Renić, Ana
AU  - Žalubovskis, Raivis
AU  - Dar'in, Dmitry
AU  - Sharoyko, Vladimir
AU  - Tennikova, Tatiana
AU  - Pešić, Milica
AU  - Krasavin, Mikhail
PY  - 2020
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3614
AB  - A series of analogs of the earlier reported lead compound DVD-445 (thioredoxin reductase inhibitor with anticancer activity) has been synthesized via a modified Ugi reaction and investigated. Seven most potent compounds (with IC50 below 5.00 μM against recombinant rTrxR1 enzyme) were examined for their effect on cell growth and viability, oxidative stress induction and P-glycoprotein (P-gp) inhibition in human glioblastoma cells cell line U87 and its corresponding multidrug resistant (MDR) cell line U87-TxR. Several of these frontrunner compounds were shown to be superior over DVD-445. Besides providing promising candidates for anticancer therapy, our study further validates the small electrophilic Ugi Michael acceptor (UMA) chemotype as efficacious inhibitor of thioredoxin reductase.
T2  - European Journal of Medicinal Chemistry
T1  - Further exploration of DVD-445 as a lead thioredoxin reductase (TrxR) inhibitor for cancer therapy: Optimization of potency and evaluation of anticancer potential.
VL  - 191
DO  - 10.1016/j.ejmech.2020.112119
SP  - 112119
ER  - 

@article{
author = "Jovanović, Mirna and Zhukovsky, Daniil and Podolski-Renić, Ana and Žalubovskis, Raivis and Dar'in, Dmitry and Sharoyko, Vladimir and Tennikova, Tatiana and Pešić, Milica and Krasavin, Mikhail",
year = "2020",
abstract = "A series of analogs of the earlier reported lead compound DVD-445 (thioredoxin reductase inhibitor with anticancer activity) has been synthesized via a modified Ugi reaction and investigated. Seven most potent compounds (with IC50 below 5.00 μM against recombinant rTrxR1 enzyme) were examined for their effect on cell growth and viability, oxidative stress induction and P-glycoprotein (P-gp) inhibition in human glioblastoma cells cell line U87 and its corresponding multidrug resistant (MDR) cell line U87-TxR. Several of these frontrunner compounds were shown to be superior over DVD-445. Besides providing promising candidates for anticancer therapy, our study further validates the small electrophilic Ugi Michael acceptor (UMA) chemotype as efficacious inhibitor of thioredoxin reductase.",
journal = "European Journal of Medicinal Chemistry",
title = "Further exploration of DVD-445 as a lead thioredoxin reductase (TrxR) inhibitor for cancer therapy: Optimization of potency and evaluation of anticancer potential.",
volume = "191",
doi = "10.1016/j.ejmech.2020.112119",
pages = "112119"
}

Jovanović, M., Zhukovsky, D., Podolski-Renić, A., Žalubovskis, R., Dar'in, D., Sharoyko, V., Tennikova, T., Pešić, M.,& Krasavin, M.. (2020). Further exploration of DVD-445 as a lead thioredoxin reductase (TrxR) inhibitor for cancer therapy: Optimization of potency and evaluation of anticancer potential.. in European Journal of Medicinal Chemistry, 191, 112119.
https://doi.org/10.1016/j.ejmech.2020.112119

Jovanović M, Zhukovsky D, Podolski-Renić A, Žalubovskis R, Dar'in D, Sharoyko V, Tennikova T, Pešić M, Krasavin M. Further exploration of DVD-445 as a lead thioredoxin reductase (TrxR) inhibitor for cancer therapy: Optimization of potency and evaluation of anticancer potential.. in European Journal of Medicinal Chemistry. 2020;191:112119.
doi:10.1016/j.ejmech.2020.112119 .

Jovanović, Mirna, Zhukovsky, Daniil, Podolski-Renić, Ana, Žalubovskis, Raivis, Dar'in, Dmitry, Sharoyko, Vladimir, Tennikova, Tatiana, Pešić, Milica, Krasavin, Mikhail, "Further exploration of DVD-445 as a lead thioredoxin reductase (TrxR) inhibitor for cancer therapy: Optimization of potency and evaluation of anticancer potential." in European Journal of Medicinal Chemistry, 191 (2020):112119,
https://doi.org/10.1016/j.ejmech.2020.112119 . .

TY  - JOUR
AU  - Jovanović, Mirna
AU  - Zhukovsky, Daniil
AU  - Podolski-Renić, Ana
AU  - Domračeva, Ilona
AU  - Žalubovskis, Raivis
AU  - Senćanski, Milan
AU  - Glišić, Sanja
AU  - Sharoyko, Vladimir
AU  - Tennikova, Tatiana
AU  - Dar'in, Dmitry
AU  - Pešić, Milica
AU  - Krasavin, Mikhail
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S0223523419307147?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3488
AB  - A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target the selenocysteine catalytic residue of thioredoxin reductase 1 (TrxR1), a promising cancer target. The compounds were assessed for their potential to inhibit TrxR1 using human neuroblastoma (SH-SY5Y) cell lysate. Based on this initial screening, six compounds were selected for testing against recombinant rat TrxR1 and in the insulin assay to reveal low-micromolar to submicromolar potency of these inhibitors. The same frontrunner compounds were evaluated for their ability to exert antiproliferative activity and induce cell death and this activity was compared to the UMA effects on the levels of reactive oxygen and nitrogen species (RONS). Collectively, the UMA compounds class presented itself as a rich source of leads for TrxR1 inhibitor discovery for anticancer application. Compound 7 (DVD-445) was nominated a lead for further optimization.
T2  - European Journal of Medicinal Chemistry
T1  - Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.
VL  - 181
DO  - 10.1016/j.ejmech.2019.111580
SP  - 111580
ER  - 

@article{
author = "Jovanović, Mirna and Zhukovsky, Daniil and Podolski-Renić, Ana and Domračeva, Ilona and Žalubovskis, Raivis and Senćanski, Milan and Glišić, Sanja and Sharoyko, Vladimir and Tennikova, Tatiana and Dar'in, Dmitry and Pešić, Milica and Krasavin, Mikhail",
year = "2019",
abstract = "A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target the selenocysteine catalytic residue of thioredoxin reductase 1 (TrxR1), a promising cancer target. The compounds were assessed for their potential to inhibit TrxR1 using human neuroblastoma (SH-SY5Y) cell lysate. Based on this initial screening, six compounds were selected for testing against recombinant rat TrxR1 and in the insulin assay to reveal low-micromolar to submicromolar potency of these inhibitors. The same frontrunner compounds were evaluated for their ability to exert antiproliferative activity and induce cell death and this activity was compared to the UMA effects on the levels of reactive oxygen and nitrogen species (RONS). Collectively, the UMA compounds class presented itself as a rich source of leads for TrxR1 inhibitor discovery for anticancer application. Compound 7 (DVD-445) was nominated a lead for further optimization.",
journal = "European Journal of Medicinal Chemistry",
title = "Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.",
volume = "181",
doi = "10.1016/j.ejmech.2019.111580",
pages = "111580"
}

Jovanović, M., Zhukovsky, D., Podolski-Renić, A., Domračeva, I., Žalubovskis, R., Senćanski, M., Glišić, S., Sharoyko, V., Tennikova, T., Dar'in, D., Pešić, M.,& Krasavin, M.. (2019). Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.. in European Journal of Medicinal Chemistry, 181, 111580.
https://doi.org/10.1016/j.ejmech.2019.111580

Jovanović M, Zhukovsky D, Podolski-Renić A, Domračeva I, Žalubovskis R, Senćanski M, Glišić S, Sharoyko V, Tennikova T, Dar'in D, Pešić M, Krasavin M. Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.. in European Journal of Medicinal Chemistry. 2019;181:111580.
doi:10.1016/j.ejmech.2019.111580 .

Jovanović, Mirna, Zhukovsky, Daniil, Podolski-Renić, Ana, Domračeva, Ilona, Žalubovskis, Raivis, Senćanski, Milan, Glišić, Sanja, Sharoyko, Vladimir, Tennikova, Tatiana, Dar'in, Dmitry, Pešić, Milica, Krasavin, Mikhail, "Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy." in European Journal of Medicinal Chemistry, 181 (2019):111580,
https://doi.org/10.1016/j.ejmech.2019.111580 . .