Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors
Конференцијски прилог (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Selective histone deacetylase 6 (HDAC6) inhibition with small molecules is regarded as
a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC
inhibitors1. To date, structural motifs that are important for HDAC inhibitory activity
and selectivity are defined as: surface recognition group (CAP group), aliphatic or
aromatic linker and zinc-binding group (ZBG).
Herein, we describe a comprehensive protocol for the computational fragment search of
novel surface-recognition (CAP) groups aimed to design selective Histone Deacetylase
6 (HDAC6) inhibitors (Figure 1)2. Identified heterocyclic CAP group, 1-benzhydryl
piperazine was employed to synthesize novel HDAC inhibitors with small structural
perturbations in the hydrocarbon linker. Enzymatic in vitro HDAC screening identified
two selective HDAC6 inhibitors (6b, IC50 = 186 nM and 9b, IC50 = 31 nM), as well as
two non-selective nanomolar HDAC inhibitors (7b and 8b). The influence of linker
chemistry o...f synthesized inhibitors on HDAC6 potency was studied using structure-based
molecular modelling.
References
1. J. Amengual, J. Lue, H. Ma, R. Lichtenstein, B. Shah, S. Cremers, S. Jones, A. Sawas,
The Oncologist, 2021, 26(3), 184 e366.
2. D. Ruzic, M. Petkovic, D. Agbaba, A. Ganesan, K. Nikolic, Mol. Inform., 2019, 38(5),
1800083.
Acknowledgments
The authors acknowledge a Ministry of Education, Science and Technological
Development of the Republic of Serbia Faculty of Pharmacy project (451-03-68/2022-
14/200161).
Извор:
8th Conference of the Young Chemists of Serbia, Book of Abstracts, 2022, 15-15Издавач:
- Serbian Chemical Society and Serbian Young Chemists’ Club
Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200161 (Универзитет у Београду, Фармацеутски факултет) (RS-MESTD-inst-2020-200161)
Напомена:
- 8th Conference of Young Chemists of Serbia 29th October 2022 Belgrade
Институција/група
PharmacyTY - CONF AU - Ružić, Dušan AU - Đoković, Nemanja AU - Srdić-Rajić, Tatjana AU - Nikolić, Katarina PY - 2022 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4737 AB - Selective histone deacetylase 6 (HDAC6) inhibition with small molecules is regarded as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors1. To date, structural motifs that are important for HDAC inhibitory activity and selectivity are defined as: surface recognition group (CAP group), aliphatic or aromatic linker and zinc-binding group (ZBG). Herein, we describe a comprehensive protocol for the computational fragment search of novel surface-recognition (CAP) groups aimed to design selective Histone Deacetylase 6 (HDAC6) inhibitors (Figure 1)2. Identified heterocyclic CAP group, 1-benzhydryl piperazine was employed to synthesize novel HDAC inhibitors with small structural perturbations in the hydrocarbon linker. Enzymatic in vitro HDAC screening identified two selective HDAC6 inhibitors (6b, IC50 = 186 nM and 9b, IC50 = 31 nM), as well as two non-selective nanomolar HDAC inhibitors (7b and 8b). The influence of linker chemistry of synthesized inhibitors on HDAC6 potency was studied using structure-based molecular modelling. References 1. J. Amengual, J. Lue, H. Ma, R. Lichtenstein, B. Shah, S. Cremers, S. Jones, A. Sawas, The Oncologist, 2021, 26(3), 184 e366. 2. D. Ruzic, M. Petkovic, D. Agbaba, A. Ganesan, K. Nikolic, Mol. Inform., 2019, 38(5), 1800083. Acknowledgments The authors acknowledge a Ministry of Education, Science and Technological Development of the Republic of Serbia Faculty of Pharmacy project (451-03-68/2022- 14/200161). PB - Serbian Chemical Society and Serbian Young Chemists’ Club C3 - 8th Conference of the Young Chemists of Serbia, Book of Abstracts T1 - Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors SP - 15 EP - 15 UR - https://hdl.handle.net/21.15107/rcub_farfar_4737 ER -
@conference{ author = "Ružić, Dušan and Đoković, Nemanja and Srdić-Rajić, Tatjana and Nikolić, Katarina", year = "2022", abstract = "Selective histone deacetylase 6 (HDAC6) inhibition with small molecules is regarded as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors1. To date, structural motifs that are important for HDAC inhibitory activity and selectivity are defined as: surface recognition group (CAP group), aliphatic or aromatic linker and zinc-binding group (ZBG). Herein, we describe a comprehensive protocol for the computational fragment search of novel surface-recognition (CAP) groups aimed to design selective Histone Deacetylase 6 (HDAC6) inhibitors (Figure 1)2. Identified heterocyclic CAP group, 1-benzhydryl piperazine was employed to synthesize novel HDAC inhibitors with small structural perturbations in the hydrocarbon linker. Enzymatic in vitro HDAC screening identified two selective HDAC6 inhibitors (6b, IC50 = 186 nM and 9b, IC50 = 31 nM), as well as two non-selective nanomolar HDAC inhibitors (7b and 8b). The influence of linker chemistry of synthesized inhibitors on HDAC6 potency was studied using structure-based molecular modelling. References 1. J. Amengual, J. Lue, H. Ma, R. Lichtenstein, B. Shah, S. Cremers, S. Jones, A. Sawas, The Oncologist, 2021, 26(3), 184 e366. 2. D. Ruzic, M. Petkovic, D. Agbaba, A. Ganesan, K. Nikolic, Mol. Inform., 2019, 38(5), 1800083. Acknowledgments The authors acknowledge a Ministry of Education, Science and Technological Development of the Republic of Serbia Faculty of Pharmacy project (451-03-68/2022- 14/200161).", publisher = "Serbian Chemical Society and Serbian Young Chemists’ Club", journal = "8th Conference of the Young Chemists of Serbia, Book of Abstracts", title = "Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors", pages = "15-15", url = "https://hdl.handle.net/21.15107/rcub_farfar_4737" }
Ružić, D., Đoković, N., Srdić-Rajić, T.,& Nikolić, K.. (2022). Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors. in 8th Conference of the Young Chemists of Serbia, Book of Abstracts Serbian Chemical Society and Serbian Young Chemists’ Club., 15-15. https://hdl.handle.net/21.15107/rcub_farfar_4737
Ružić D, Đoković N, Srdić-Rajić T, Nikolić K. Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors. in 8th Conference of the Young Chemists of Serbia, Book of Abstracts. 2022;:15-15. https://hdl.handle.net/21.15107/rcub_farfar_4737 .
Ružić, Dušan, Đoković, Nemanja, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors" in 8th Conference of the Young Chemists of Serbia, Book of Abstracts (2022):15-15, https://hdl.handle.net/21.15107/rcub_farfar_4737 .