Page 100 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

POSTER SESSION

SESSION 1

BENEFITS OF COMBINATION THERAPIES IN CANCER TREATMENT

P01

Identification of Dual-Acting HDAC Inhibitors for Pancreatic Cancer Treatment through Drug Synergy
Predictions and Molecular Modeling

Nemanja Djokovic , Aleksandra Ilic , Alen Cebzan , Branko Radovic , Dusan Ruzic , Milan Beljkas , Ana Djuric , Tatjana
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Srdic-Rajic , Slavica Oljacic , and Katarina Nikolic 1
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1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
2Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia
Keywords: drug design, polypharmacology, antineoplastic agents
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers,
with chemoresistance playing a significant role in its poor prognosis. This highlights the urgent need for the
development of novel therapeutic strategies to overcome resistance and improve treatment outcomes for
PDAC. Considering the widespread epigenetic alterations in PDAC, targeting epigenetic regulators such as
histone deacetylases (HDACs) with inhibitors is a promising approach, especially in combination therapies.
Material and Methods: In this study, we developed a bioinformatic screening protocol to
predict potential synergistic combinations of HDAC inhibitors, including sirtuin (SIRT) inhibitors,
by utilizing data on drug sensitivity and basal gene expression of pancreatic cancer cell lines.
Results and Conclusions: Experimental validation in two pancreatic cancer cell lines, MIA PaCa-
2 and PANC-1, confirmed synergy between HDAC inhibitors and either the sphingosine-1-phosphate
(S1P) receptor agonist fingolimod or the Rho-associated protein kinase (ROCK) inhibitor RKI-1447.
The bioinformatic screening also identified several previously unknown interaction partners for HDAC inhibitors,
including ROCK, aurora kinase A (AURKA), glutaminase 1(GLS1) and WEE1 kinase inhibitors. These identified
interactions were further investigated using structure-based molecular modeling to develop novel dual-acting
HDAC inhibitors (HDAC/ROCK, SIRT/AURKA, HDAC/GLS1 and HDAC/WEE1). The molecular docking simulations
revealed strong binding affinities of the novel dual-acting HDAC inhibitors to the respective targets. The key
structural features responsible for the inhibition of HDAC1/4/6/8, SIRT, ROCK1, ROCK2, AURKA, GLS1 and
WEE1 were identified and served as the basis for the development of these dual-acting HDAC inhibitors.
Together with the predictions of drug synergies, these inhibitors prove to be promising candidates for future
experimental validation. The most promising dual-acting HDAC inhibitors identified in silico will be synthesized for
further in vitro enzyme and cell-based assays.

Acknowledgments and funding: This research was funded by the Ministry of Education, Science and Technological
Development, Republic of Serbia through Grant Agreement with the University of Belgrade-Faculty of Pharmacy No:
451-03-65/2024-03/200161. The authors thank the COST Actions CA18240, CA21135 and CA22125 of the European
Community for support.

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