Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling
Authors
Đoković, Nemanja
Ilić, Aleksandra
Čebzan, Alen

Radović, Branko
Ružić, Dušan

Đurić, Ana

Srdić-Rajić, Tatjana

Nikolić, Katarina

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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 li...nes (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.
Source:
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, 47-47Publisher:
- International Association of Physical Chemists
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- 10th IAPC Meeting, Book of Abstracts
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PharmacyTY - 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 .