Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study
Autori
Ružić, DušanPetković, Miloš
Đoković, Nemanja
Santibanez, Juan
Pavić, Aleksandar
Ganesan, A.
Srdić Rajić, Tatjana
Nikolić, Katarina
Konferencijski prilog (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that has poor survival rates due to the absence of specific molecular markers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In the era of precision oncology, it is recognized that an imbalance in post-translational modifications of histones, such as histone lysine acetylation and deacetylation, is closely linked to tumor initiation and progression. Two groups of enzymes control the reversible nature of histone post-translational acetylation: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Isoform-specific targeting of HDACs is considered a rational strategy to develop safe anticancer therapeutics compared to non-selective HDAC inhibitors. However, non-selective HDAC inhibitors have been more extensively studied in clinical trials. This work presents the design and discovery of potent HDAC inhibitors that selectively target HD...AC6 isozyme, using 1-benzhydryl piperazine as a surface recognition group with different hydrocarbon linkers. Through in vitro screening, two HDAC6-selective inhibitors with nanomolar IC50 values and two non-selective HDAC inhibitors were identified. Structure-based molecular modelling was utilized to investigate the impact of linker chemistry on the potency of synthesized inhibitors against HDAC6. The anti-cancer, anti-migratory, and anti-invasive activities of these compounds were evaluated using breast cancer cell lines (MDA-MB-231 and MCF-7). Experiments on a zebrafish MDA-MB-231 xenograft model demonstrated that a novel non-selective HDAC inhibitor (8b) with a seven-carbon-atom linker exhibited potent effects against tumor growth, metastasis, and angiogenesis at low micromolar concentrations.
Ključne reči:
anticancer drug / breast cancer / histone deacetylases / hydroxamic acidIzvor:
Oncology Insights, 2023, 1Izdavač:
- Serbian Association on for Cancer Research Belgrade, Serbia
Finansiranje / projekti:
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200161 (Univerzitet u Beogradu, Farmaceutski fakultet) (RS-MESTD-inst-2020-200161)
Napomena:
- Proceedings of the 6th Congress of SDIR: From Collaboration to Innovation in Cancer Research, 2nd – 4th October 2023, Belgrade
Institucija/grupa
PharmacyTY - CONF AU - Ružić, Dušan AU - Petković, Miloš AU - Đoković, Nemanja AU - Santibanez, Juan AU - Pavić, Aleksandar AU - Ganesan, A. AU - Srdić Rajić, Tatjana AU - Nikolić, Katarina PY - 2023 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5074 AB - Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that has poor survival rates due to the absence of specific molecular markers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In the era of precision oncology, it is recognized that an imbalance in post-translational modifications of histones, such as histone lysine acetylation and deacetylation, is closely linked to tumor initiation and progression. Two groups of enzymes control the reversible nature of histone post-translational acetylation: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Isoform-specific targeting of HDACs is considered a rational strategy to develop safe anticancer therapeutics compared to non-selective HDAC inhibitors. However, non-selective HDAC inhibitors have been more extensively studied in clinical trials. This work presents the design and discovery of potent HDAC inhibitors that selectively target HDAC6 isozyme, using 1-benzhydryl piperazine as a surface recognition group with different hydrocarbon linkers. Through in vitro screening, two HDAC6-selective inhibitors with nanomolar IC50 values and two non-selective HDAC inhibitors were identified. Structure-based molecular modelling was utilized to investigate the impact of linker chemistry on the potency of synthesized inhibitors against HDAC6. The anti-cancer, anti-migratory, and anti-invasive activities of these compounds were evaluated using breast cancer cell lines (MDA-MB-231 and MCF-7). Experiments on a zebrafish MDA-MB-231 xenograft model demonstrated that a novel non-selective HDAC inhibitor (8b) with a seven-carbon-atom linker exhibited potent effects against tumor growth, metastasis, and angiogenesis at low micromolar concentrations. PB - Serbian Association on for Cancer Research Belgrade, Serbia C3 - Oncology Insights T1 - Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study VL - 1 UR - https://hdl.handle.net/21.15107/rcub_farfar_5074 ER -
@conference{ author = "Ružić, Dušan and Petković, Miloš and Đoković, Nemanja and Santibanez, Juan and Pavić, Aleksandar and Ganesan, A. and Srdić Rajić, Tatjana and Nikolić, Katarina", year = "2023", abstract = "Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that has poor survival rates due to the absence of specific molecular markers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In the era of precision oncology, it is recognized that an imbalance in post-translational modifications of histones, such as histone lysine acetylation and deacetylation, is closely linked to tumor initiation and progression. Two groups of enzymes control the reversible nature of histone post-translational acetylation: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Isoform-specific targeting of HDACs is considered a rational strategy to develop safe anticancer therapeutics compared to non-selective HDAC inhibitors. However, non-selective HDAC inhibitors have been more extensively studied in clinical trials. This work presents the design and discovery of potent HDAC inhibitors that selectively target HDAC6 isozyme, using 1-benzhydryl piperazine as a surface recognition group with different hydrocarbon linkers. Through in vitro screening, two HDAC6-selective inhibitors with nanomolar IC50 values and two non-selective HDAC inhibitors were identified. Structure-based molecular modelling was utilized to investigate the impact of linker chemistry on the potency of synthesized inhibitors against HDAC6. The anti-cancer, anti-migratory, and anti-invasive activities of these compounds were evaluated using breast cancer cell lines (MDA-MB-231 and MCF-7). Experiments on a zebrafish MDA-MB-231 xenograft model demonstrated that a novel non-selective HDAC inhibitor (8b) with a seven-carbon-atom linker exhibited potent effects against tumor growth, metastasis, and angiogenesis at low micromolar concentrations.", publisher = "Serbian Association on for Cancer Research Belgrade, Serbia", journal = "Oncology Insights", title = "Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study", volume = "1", url = "https://hdl.handle.net/21.15107/rcub_farfar_5074" }
Ružić, D., Petković, M., Đoković, N., Santibanez, J., Pavić, A., Ganesan, A., Srdić Rajić, T.,& Nikolić, K.. (2023). Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study. in Oncology Insights Serbian Association on for Cancer Research Belgrade, Serbia., 1. https://hdl.handle.net/21.15107/rcub_farfar_5074
Ružić D, Petković M, Đoković N, Santibanez J, Pavić A, Ganesan A, Srdić Rajić T, Nikolić K. Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study. in Oncology Insights. 2023;1. https://hdl.handle.net/21.15107/rcub_farfar_5074 .
Ružić, Dušan, Petković, Miloš, Đoković, Nemanja, Santibanez, Juan, Pavić, Aleksandar, Ganesan, A., Srdić Rajić, Tatjana, Nikolić, Katarina, "Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study" in Oncology Insights, 1 (2023), https://hdl.handle.net/21.15107/rcub_farfar_5074 .