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Discovery of Alkoxy Benzamide Derivatives As Novel BPTF

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Discovery of Alkoxy Benzamide Derivatives As Novel BPTF Bioorganic Chemistry 86 (2019) 494–500 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg Discovery of alkoxy benzamide derivatives as novel BPTF bromodomain T inhibitors via structure-based virtual screening Dan Zhanga,b,i,1, Jie Hanb,c,i,1, Wenchao Lub,c,i,1, Fulin Lianb,c, Jun Wangb,d, Tian Lub,d, Hongru Taob,e, Senhao Xiaob,g, Fengcai Zhangb,h, Yu-Chih Liuf, Rongfeng Liuf, Naixia Zhangb,c, ⁎ ⁎ Hualiang Jiangb,c,g,i, Kaixian Chenb,c,g,i, Chunshen Zhaoa, , Cheng Luob,c,g,i, a Guizhou Engineering Laboratory for Synthetic Drugs, Key Laboratory of Guizhou for Fermentation Engineering and Biomedicine, School of Pharmaceutical Sciences, Guizhou University, Guizhou 550025, China b State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China c University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China d Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China e School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai 200444, China f Shanghai ChemPartner Co., LTD., Zhangjiang Hi-Tech Park, Shanghai 201203, China g School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China h School of Pharmacy, Nanchang University, 461 Bayi Road, Nanchang 330006, China i Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China ARTICLE INFO ABSTRACT Keywords: Bromodomain PHD finger transcription factor (BPTF), a bromodomain-containing protein, plays a crucial rolein Lysine acetylation the regulation of downstream gene expression through the specific recognition of lysine acetylation on bulk Bromodomain histones. The dysfunction of BPTF is closely involved with the development and progression of many human Virtual screening diseases, especially cancer. Therefore, BPTF bromodomain has become a promising drug target for epigenetic BPTF inhibitor cancer therapy. However, unlike BET family inhibitors, few BPTF bromodomain inhibitors have been reported. In this study, by integrating docking-based virtual screening with biochemical analysis, we identified a novel selective BPTF bromodomain inhibitor DCB29 with the IC50 value of 13.2 ± 1.6 μM by homogenous time- resolved fluorescence resonance energy transfer (HTRF) assays. The binding between DCB29 and BPTF was confirmed by NMR and SPR. Molecular docking disclosed that DCB29 occupied the pocket of acetylated H4 peptide substrate and provided detailed SAR explanations for its derivatives. Collectively, DCB29 presented great potential as a powerful tool for BPTF-related biological research and further medicinal chemistry opti- mization. 1. Introduction bromodomain (BRD) family. So far 61 BRDs have been identified and could be categorized into eight distinct families according to their re- Lysine acetylation on bulk histones regulates the chromatin archi- lative functions [1]: HAT component (GCN5, PCAF, etc.), ATP-depen- tecture and access to DNA, which has emerged as the best-characterized dent chromatin remodeling complex component (BAZ1B, etc.), helicase post-translational modification (PTM) in epigenetic research. The component (SMARCA), methyltransferase component (MLL, ASH1L, acetylated lysine in histones could be specifically recognized by etc.), transcriptional co-activation factor components (TRIM, TAF, etc.), Abbreviations: BPTF, bromodomain PHD finger transcription factor; HTRF, homogenous time-resolved fluorescence resonance energy transfer; PTM, post-trans- lational modification; BCPs, bromodomain-containing proteins; SPR, surface plasmon resonance assays; PAINS, pan assay interference compounds; GST, glutathione S-transferase; SP, standard precision; BRD, bromodomain; CPMG, Carr-Purcell-Meiboom-Gill; ALPHA, amplified luminescent proximity homogeneous assay; NMR, nuclear magnetic resonance ⁎ Corresponding authors at: State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China (C. Luo). E-mail address: [email protected] (C. Luo). 1 These authors contributed equally. https://doi.org/10.1016/j.bioorg.2019.01.035 Received 25 October 2018; Received in revised form 10 January 2019; Accepted 21 January 2019 Available online 28 January 2019 0045-2068/ © 2019 Elsevier Inc. All rights reserved. D. Zhang, et al. Bioorganic Chemistry 86 (2019) 494–500 Fig. 1. Representatives of small-molecule inhibitors targeting BCPs. transcriptional mediator component (TAF1), nuclear skeleton protein at micromolar levels. However, it’s more potent against other BRDs component (PB1), and BET family component (BRD2/3/4/T) [2]. including BRD2, BRD4, BRD9, and CECR2 [27]. Therefore, there is The earliest BRD structure was determined by NMR-imaging in urgent need to develop potent and selective BPTF bromodomain in- 1990 by Haynes and co-workers [3,4]. The BRD family was found to hibitors with novel scaffolds for BPTF-related mechanism studies. have a conserved hydrophobic pocket surrounded by four reverse α- In this work, through docking-based virtual screening, we identified helices bundles (αZ, αA, αB, αC) [5]. The bromodomain-containing a novel, selective BPTF bromodomain inhibitor DCB29 with the IC50 proteins (BCPs) can thus act as “readers” of acetylated histones re- value of 13.2 ± 1.6 μM measured by HTRF. DCB29 displayed high cruiting related chromatin remodeling factors and transcription factors selectivity over other BCPs and epi-targets. Further biophysical assays to specific gene transcription sites, which is essential for downstream like NMR and surface plasmon resonance assays (SPR) also confirmed gene expression [6,7]. the direct binding between DCB29 and BPTF bromodomain. Further Aberrant expression and activation of BCPs have been implicated in molecular docking results demonstrated that DCB29 occupied the the development and progression of many diseases, such as obesity [8], pocket of H4 peptide substrate, which disclosed the molecular me- HIV [9], malignant cancers and inflammation [10-12]. Hitherto, a large chanism of its inhibitory activity. number of small-molecule inhibitors targeting BCPs have been devel- oped for the treatment of BCPs-related diseases and could be used as 2. Results and discussion functional chemical probes to explore the biological function of BCPs (Fig. 1). 2.1. Structure-based virtual screening Among BCPs, bromodomain and extra-terminal domain (BET) fa- mily was most well-studied in both academia and industry due to its Nowadays, with the rapid development of computational meth- unique role in the maintenance of higher-order architecture of chro- odologies, virtual screening has been widely applied for the discovery matin and the regulation of oncogenes transcriptional activation in- of lead compounds in both academia and industry. It has become a cluding MYC. BET family inhibitors OTX-015 and I-BET762 have suc- powerful and efficient tool and made great achievement in epigenetic- cessfully entered into clinical trials for the treatment of leukemia and related research in recent decades [28-31]. Herein, docking-based vir- solid tumors [13,14]. Instead, compared to impressive progress in the tual screening was performed to identify novel BPTF inhibitors from the drug discovery and development for BET family, the development of in-house compound library, which has been optimized by Lipinski’s rule potent and selective inhibitors for non-BET BCPs lags behind. Bromo- of five [32] and “pan-assay interference compounds” rules [33-35] domain PHD finger transcription factor (BPTF), which contains anon- using Pipeline Pilot, version 7.5 (Pipeline Pilot; Accelrys Software Inc., BET bromodomain motif, plays a pivotal role in chromatin remodeling San Diego, CA) based on SPECS chemical database (Fig. 2). An indexed [15,16], transcriptional regulation [17], cell differentiation [18], em- multi-conformer 3D database containing 20,000 compounds derived bryogenesis [19], and so on. Dysfunction of BPTF has been reported to from preprocessed compound library with all stereoisomers and dif- be associated with the development and progression of malignant ferent protonation states was generated in Accelrys Discovery Studio cancers including bladder cancer [20], colorectal cancer [21], mela- 3.0 as previously described by Meng et al [28,36]. Based on human noma [22,23], leukemia [24] and so on. Knockdown of BPTF enhances crystal structure of BPTF bromodomain (PDB: 3QZS), residues located anti-tumor immunity mediated by CD8+ T cell or NK cell [25]. Col- within 10 Å of N148 were defined as the binding pocket. Then mole- lectively, BPTF has emerged as the novel anti-cancer drug target for cular docking was performed using Glide SP mode integrated in chemical intervention in the era of target therapy. Maestro [37]. The top-ranked 1000 candidates were selected for further Nonetheless, little progress has been achieved in the drug discovery cluster analysis and visual inspection to rule out the compounds with against the BPTF bromodomain. Mishra and co-workers reported that poor shape and repeated chemical scaffold. Finally, 105 compounds BI-2536 binds to 5FW-BPTF by a 19F NMR method using
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