Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors

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).