TY  - JOUR
AU  - Beljkaš, Milan
AU  - Ilić, Aleksandra
AU  - Cebzan, Alen
AU  - Radović, Branko
AU  - Đoković, Nemanja
AU  - Ružić, Dušan
AU  - Nikolić, Katarina
AU  - Oljačić, Slavica
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5339
AB  - Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies. As a result, HDAC6 is considered a promising target for cancer treatment. However, none of selective HDAC6 inhibitors are in clinical use, mainly because of the low efficacy and high concentrations used to show anticancer properties, which may lead to off-target effects. Therefore, HDAC6 inhibitors with dual-target capabilities represent a new trend in cancer treatment, aiming to overcome the above problems. In this review, we summarize the advances in tumor treatment with dual-target HDAC6 inhibitors.
PB  - MDPI
T2  - Pharmaceutics
T1  - Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer
VL  - 15
IS  - 11
DO  - 10.3390/pharmaceutics15112581
ER  - 

@article{
author = "Beljkaš, Milan and Ilić, Aleksandra and Cebzan, Alen and Radović, Branko and Đoković, Nemanja and Ružić, Dušan and Nikolić, Katarina and Oljačić, Slavica",
year = "2023",
abstract = "Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies. As a result, HDAC6 is considered a promising target for cancer treatment. However, none of selective HDAC6 inhibitors are in clinical use, mainly because of the low efficacy and high concentrations used to show anticancer properties, which may lead to off-target effects. Therefore, HDAC6 inhibitors with dual-target capabilities represent a new trend in cancer treatment, aiming to overcome the above problems. In this review, we summarize the advances in tumor treatment with dual-target HDAC6 inhibitors.",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer",
volume = "15",
number = "11",
doi = "10.3390/pharmaceutics15112581"
}

Beljkaš, M., Ilić, A., Cebzan, A., Radović, B., Đoković, N., Ružić, D., Nikolić, K.,& Oljačić, S.. (2023). Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer. in Pharmaceutics
MDPI., 15(11).
https://doi.org/10.3390/pharmaceutics15112581

Beljkaš M, Ilić A, Cebzan A, Radović B, Đoković N, Ružić D, Nikolić K, Oljačić S. Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer. in Pharmaceutics. 2023;15(11).
doi:10.3390/pharmaceutics15112581 .

Beljkaš, Milan, Ilić, Aleksandra, Cebzan, Alen, Radović, Branko, Đoković, Nemanja, Ružić, Dušan, Nikolić, Katarina, Oljačić, Slavica, "Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer" in Pharmaceutics, 15, no. 11 (2023),
https://doi.org/10.3390/pharmaceutics15112581 . .

TY  - CONF
AU  - Đoković, Nemanja
AU  - Ilić, Aleksandra
AU  - Čebzan, Alen
AU  - Radović, Branko
AU  - Ružić, Dušan
AU  - Đurić, Ana
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5001
AB  - Pancreatic ductal adenocarcinoma (PDAC) ranks among the most formidable and deadly
types of cancer. The emergence of chemoresistance in PDAC plays a significant role in the
unfavorable survival rates, making it imperative to swiftly develop new pharmaceutical
strategies to address this issue and improve treatment outcomes for PDAC (1). Considering
the numerous epigenetic changes observed in PDAC, the utilization of epigenetic drugs,
such as histone deacetylase (HDAC) inhibitors, holds a great promise as a transformative
approach, particularly when used in combination therapy settings (2).
In this study, we investigated the potential of utilizing drug sensitivity data and the basal
gene expression of pancreatic carcinoma cell lines to develop a bioinformatics screening
protocol for prediction of the combinatorial options available for HDAC inhibitors, including
sirtuin (SIRT) inhibitors. Experimental validation of the protocol performed on the two
pancreatic carcinoma cell lines (MIA PaCa-2 cells and PANC-1) confirmed the identified
synergisms between HDAC inhibitors and sphingosine 1-phosphate (S1P) receptor agonist
– fingolimod, or HDAC inhibitors and Rho-associated protein kinase (ROCK) inhibitor – RKI1447 (3).
Developed bioinformatics screening protocol for predictions of synergistic drug
combinations in PDAC identified several previously unreported interaction partners of
HDAC inhibitors. Predicted interaction partners of HDAC inhibitors including Aurora Kinase
A (AURKA) inhibitor, glutaminase (GLS) inhibitor and WEE1 kinase inhibitor were selected
for the design of novel classes of dual-acting HDAC inhibitors by the means of structure-based molecular modelling. Novel dual inhibitors (SIRT/AURKA, HDAC/GLS and HDAC/WEE1)
were designed relying on the known pharmacophoric features and molecular docking
models developed for each of the targets of interest. The docking scores of the designed
inhibitors revealed a notable affinity towards the specific targets. Additionally, when
combined with predictions of drug synergy, these designed molecules exhibit great
potential as promising structures for subsequent experimental evaluation.
PB  - International Association of Physical Chemists
C3  - 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6
T1  - Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling
SP  - 47
EP  - 47
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5001
ER  - 

@conference{
author = "Đoković, Nemanja and Ilić, Aleksandra and Čebzan, Alen and Radović, Branko and Ružić, Dušan and Đurić, Ana and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2023",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) ranks among the most formidable and deadly
types of cancer. The emergence of chemoresistance in PDAC plays a significant role in the
unfavorable survival rates, making it imperative to swiftly develop new pharmaceutical
strategies to address this issue and improve treatment outcomes for PDAC (1). Considering
the numerous epigenetic changes observed in PDAC, the utilization of epigenetic drugs,
such as histone deacetylase (HDAC) inhibitors, holds a great promise as a transformative
approach, particularly when used in combination therapy settings (2).
In this study, we investigated the potential of utilizing drug sensitivity data and the basal
gene expression of pancreatic carcinoma cell lines to develop a bioinformatics screening
protocol for prediction of the combinatorial options available for HDAC inhibitors, including
sirtuin (SIRT) inhibitors. Experimental validation of the protocol performed on the two
pancreatic carcinoma cell lines (MIA PaCa-2 cells and PANC-1) confirmed the identified
synergisms between HDAC inhibitors and sphingosine 1-phosphate (S1P) receptor agonist
– fingolimod, or HDAC inhibitors and Rho-associated protein kinase (ROCK) inhibitor – RKI1447 (3).
Developed bioinformatics screening protocol for predictions of synergistic drug
combinations in PDAC identified several previously unreported interaction partners of
HDAC inhibitors. Predicted interaction partners of HDAC inhibitors including Aurora Kinase
A (AURKA) inhibitor, glutaminase (GLS) inhibitor and WEE1 kinase inhibitor were selected
for the design of novel classes of dual-acting HDAC inhibitors by the means of structure-based molecular modelling. Novel dual inhibitors (SIRT/AURKA, HDAC/GLS and HDAC/WEE1)
were designed relying on the known pharmacophoric features and molecular docking
models developed for each of the targets of interest. The docking scores of the designed
inhibitors revealed a notable affinity towards the specific targets. Additionally, when
combined with predictions of drug synergy, these designed molecules exhibit great
potential as promising structures for subsequent experimental evaluation.",
publisher = "International Association of Physical Chemists",
journal = "10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6",
title = "Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling",
pages = "47-47",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5001"
}

Đoković, N., Ilić, A., Čebzan, A., Radović, B., Ružić, D., Đurić, A., Srdić-Rajić, T.,& Nikolić, K.. (2023). Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling. in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6
International Association of Physical Chemists., 47-47.
https://hdl.handle.net/21.15107/rcub_farfar_5001

Đoković N, Ilić A, Čebzan A, Radović B, Ružić D, Đurić A, Srdić-Rajić T, Nikolić K. Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling. in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6. 2023;:47-47.
https://hdl.handle.net/21.15107/rcub_farfar_5001 .

Đoković, Nemanja, Ilić, Aleksandra, Čebzan, Alen, Radović, Branko, Ružić, Dušan, Đurić, Ana, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling" in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6 (2023):47-47,
https://hdl.handle.net/21.15107/rcub_farfar_5001 .

TY  - CONF
AU  - Radović, Branko
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3851
AB  - Хистон деацетилазе (HDAC) су ензими који катализују деацетилацију лизинских остатака хистона, али је потврђено да деацетилују и протеине изван једра. Изоформа која хидролизује ацетил групе са не-хистонских протеина је хистон деацетилаза 6 (HDAC6), која је цинк-зависна металопротеаза и доминантно се налази у цитоплазми. Познато је да HDAC6 изоформа може да иницира процесе туморогенезе, неоангиогенезе и транзицију појединих врста канцерских ћелија ка метастатском фенотипу. Данас се у онколошкој терапији примењују неселективни HDAC инхибитори (пан-HDAC инхибитори), али због појединих нежељених дејстава неселективних инхибитора, селективна инхибиција HDAC6 инхибитора представља обећавајућу стратегију у развоју нових антиканцерских лекова. HDAC инхибитори се састоје из хетероцикличног носача (CAP групе), линкера и цинк-везивне групе (ZBG), при чему се увођењем волуминозне CAP групе, повећава селективност ка HDAC6 изоформи.
AB  - Histone deacetylases (HDACs) are enzymes which perform deacetylation of lysine residues of histones, but it has been discovered they deacetylase some proteins outside of the nucleus. Isoform that is conducting these deacetylations is histone deacetylase 6 (HDAC6), which is zinc-dependent metalloprotease and it is predominantly located in the cytoplasm. It has been known that HDAC6 isoform can initiate processes such as tumorigenesis, neoangiogenesis and transition of some cancer cell lines towards metastasis. Today, nonselective HDAC inhibitors (pan-HDAC inhibitors) are being used in cancer treatment, but due to some of their side effects, selective inhibition of HDAC6 is regarded as promising strategy in development of new anticancer drugs. HDAC inhibitors are consisted from heterocyclic carrier (CAP group), linker and zinc-binding group (ZBG), whereby selectivity towards HDAC6 isoform is increased by introduction of bulky CAP groups.
T1  - Синтеза и молекулско моделовање новог деривата фенитоина као потенцијалног инхибитора хумане хистон деацетилазе 6
T1  - Synthesis and molecular modeling of new phenytoin derivative as promising histone deacetylase 6 inhibitor
UR  - https://hdl.handle.net/21.15107/rcub_farfar_3851
ER  - 

@conference{
author = "Radović, Branko",
year = "2021",
abstract = "Хистон деацетилазе (HDAC) су ензими који катализују деацетилацију лизинских остатака хистона, али је потврђено да деацетилују и протеине изван једра. Изоформа која хидролизује ацетил групе са не-хистонских протеина је хистон деацетилаза 6 (HDAC6), која је цинк-зависна металопротеаза и доминантно се налази у цитоплазми. Познато је да HDAC6 изоформа може да иницира процесе туморогенезе, неоангиогенезе и транзицију појединих врста канцерских ћелија ка метастатском фенотипу. Данас се у онколошкој терапији примењују неселективни HDAC инхибитори (пан-HDAC инхибитори), али због појединих нежељених дејстава неселективних инхибитора, селективна инхибиција HDAC6 инхибитора представља обећавајућу стратегију у развоју нових антиканцерских лекова. HDAC инхибитори се састоје из хетероцикличног носача (CAP групе), линкера и цинк-везивне групе (ZBG), при чему се увођењем волуминозне CAP групе, повећава селективност ка HDAC6 изоформи., Histone deacetylases (HDACs) are enzymes which perform deacetylation of lysine residues of histones, but it has been discovered they deacetylase some proteins outside of the nucleus. Isoform that is conducting these deacetylations is histone deacetylase 6 (HDAC6), which is zinc-dependent metalloprotease and it is predominantly located in the cytoplasm. It has been known that HDAC6 isoform can initiate processes such as tumorigenesis, neoangiogenesis and transition of some cancer cell lines towards metastasis. Today, nonselective HDAC inhibitors (pan-HDAC inhibitors) are being used in cancer treatment, but due to some of their side effects, selective inhibition of HDAC6 is regarded as promising strategy in development of new anticancer drugs. HDAC inhibitors are consisted from heterocyclic carrier (CAP group), linker and zinc-binding group (ZBG), whereby selectivity towards HDAC6 isoform is increased by introduction of bulky CAP groups.",
title = "Синтеза и молекулско моделовање новог деривата фенитоина као потенцијалног инхибитора хумане хистон деацетилазе 6, Synthesis and molecular modeling of new phenytoin derivative as promising histone deacetylase 6 inhibitor",
url = "https://hdl.handle.net/21.15107/rcub_farfar_3851"
}

Radović, B.. (2021). Синтеза и молекулско моделовање новог деривата фенитоина као потенцијалног инхибитора хумане хистон деацетилазе 6. .
https://hdl.handle.net/21.15107/rcub_farfar_3851

Radović B. Синтеза и молекулско моделовање новог деривата фенитоина као потенцијалног инхибитора хумане хистон деацетилазе 6. 2021;.
https://hdl.handle.net/21.15107/rcub_farfar_3851 .

Radović, Branko, "Синтеза и молекулско моделовање новог деривата фенитоина као потенцијалног инхибитора хумане хистон деацетилазе 6" (2021),
https://hdl.handle.net/21.15107/rcub_farfar_3851 .