@conference{
author = "Đoković, Nemanja and Ilić, Aleksandra and Čebzan, Alen and Radović, Branko and Ružić, Dušan and Beljkaš, Milan and Đurić, Ana and Srdić-Rajić, Tatjana and Oljačić, Slavica and Nikolić, Katarina",
year = "2024",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) is one of the most threatening and deadly cancers. The occurrence of
chemoresistance in PDAC plays an important role in the unfavorable survival rates, so there is an urgent need to
rapidly develop new pharmaceutical strategies to address this problem and improve treatment outcomes for
PDAC (1). Considering the numerous epigenetic alterations observed in PDAC, the use of epigenetic drugs, such
as histone deacetylase (HDAC) inhibitors, is a promising approach, especially when used in combination
therapies (2).
In this study, we investigated the potential of using drug sensitivity and basal gene expression data from
pancreatic cancer cell lines to develop a bioinformatic screening protocol to predict the available combinatorial
options for HDAC inhibitors, including sirtuin (SIRT) inhibitors. Experimental validation of the protocol in two
pancreatic cancer cell lines (MIA PaCa-2 cells and PANC-1) confirmed the identified synergies between HDAC
inhibitors and the sphingosine-1-phosphate (S1P) receptor agonist – fingolimod or HDAC inhibitors and the
Rho-associated protein kinase (ROCK) inhibitor – RKI-1447 (3).
The bioinformatic screening protocol developed to predict synergistic drug combinations in PDAC identified
several previously unknown interaction partners of HDAC inhibitors. The predicted interaction partners of
HDAC inhibitors, including ROCK, aurora kinase A inhibitor (AURKA), glutaminase inhibitor (GLS) and
WEE1 kinase inhibitor, were selected using structure-based molecular modeling for the development of novel
classes of dual-acting HDAC inhibitors. The novel dual inhibitors (HDAC/ROCK, SIRT/AURKA, HDAC/GLS
and HDAC/WEE1) were designed based on the known pharmacophore properties and molecular docking models
developed for the respective targets. The molecular docking study was performed using GOLD software. The
enzymes were prepared for the docking study using the online software Play Molecule-ProteinPrepare. The
docking results of the developed inhibitors showed a remarkable affinity to the specific targets. The critical parts
of the structures that produce the interactions crucial for the inhibition of HDAC1, HDAC6, ROCK1, ROCK2,
AURKA, GLS and WEE1 were identified. In conjunction with the drug synergy predictions, these designed
molecules also show great potential as promising structures for subsequent experimental evaluation. Taking all
these findings into account, the most aactive compounds were selected to be further synthesized and evaluated
using in vitro enzyme and cell assays.
References
1) A. McGuigan et al., World J Gastroenterol. 24, 4846–4861 (2018).
2) X.-S. Xiang, P.-C. Li, W.-Q. Wang, L. Liu, Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1877, 188676
(2022).
3) N. Djokovic, A. Djuric, D. Ruzic, T. Srdic-Rajic, K. Nikolic, Pharmaceuticals. 16, 294 (2023).",
publisher = "EFMC, Societa Chimica Italiana",
journal = "EFMC-ISMC 2024, XXVIII EFMC International Symposium on Medicinal Chemistry, Rome, Italy, September 1-5, 2024, Book of Abstracts",
title = "Discovery of dual-acting HDAC inhibitors for the treatment of pancreatic cancer by combining drug synergy and molecular modeling",
pages = "463-463",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5747"
}
