Drug Discovery of Acetophenone Derivatives as BRD4 Inhibitors

Author(s): Zhimin Zhang, Wenhai Huang, Xiaoliang Zheng, Chuansheng Li, Zhengrong Shen*

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 3 , 2020

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Graphical Abstract:


Background: The bromodomain and extra-terminal proteins (BET), in particular BRD4, has recently emerged as a potential therapeutic target for the treatment of many human disorders such as cancer, inflammation, obesity and cardiovascular disease, which draw more and more attention to discover potent BRD4 inhibitors in the past years. In this article, we described the discovery process of an entirely new chemotype of BRD4 inhibitors.

Methods: A fragment-based drug discovery strategy was employed in attempting to find a novel chemotype of BRD4 inhibitors. Thus, the potential hits were firstly identified by docking study with KAc binding pocket and AlphaScreen assay. Then the elected hit was further structurally optimized based on the interaction revealed by the docking study and the Structure-Activity Relationship (SAR).

Results: A 1-(2-hydroxyphenyl)ethan-1-one fragment was first identified as an efficient hit to BRD4 with a weak inhibition activity and high ligand efficiency (IC50 = 8.9 μM, LE > 0.5) based on virtual screening and biochemical assay. Then, two-rounds optimization of the hit by a fragmentbased drug discovery approach enabled the discovery of a potent BRD4 inhibitor 9, which exhibit nanomolar potency in biochemical assays (IC50 = 0.18 μM).

Conclusion: The title compounds displayed potent inhibitory activity to BRD4, implying acetophenone core is an effective KAc residue mimic, suggesting acetophenone derivatives as a new chemotype may be promising for developing novel BRD4 inhibitors.

Keywords: Fragment-based drug discovery, rational drug design, BRD4 bromodomain, synthesis, acetophenone derivatives, epigenetic.

Huang, W.; Zheng, X.; Yang, Y.; Wang, X.; Shen, Z. An overview on small molecule inhibitors of BRD4. Mini Rev. Med. Chem., 2016, 16(17), 1403-1414.
[http://dx.doi.org/10.2174/1389557516666160611014130] [PMID: 27290915]
Jain, A.K.; Barton, M.C. Bromodomain histone readers and cancer. J. Mol. Biol., 2017, 429(13), 2003-2010.
[http://dx.doi.org/10.1016/j.jmb.2016.11.020] [PMID: 27890782]
Smith, S.G.; Zhou, M.M. The bromodomain: A new target in emerging epigenetic medicine. ACS Chem. Biol., 2016, 11(3), 598-608.
[http://dx.doi.org/10.1021/acschembio.5b00831] [PMID: 26596782]
Devaiah, B.N.; Gegonne, A.; Singer, D.S. Bromodomain 4: A cellular Swiss army knife. J. Leukoc. Biol., 2016, 100(4), 679-686.
[http://dx.doi.org/10.1189/jlb.2RI0616-250R] [PMID: 27450555]
Padmanabhan, B.; Mathur, S.; Manjula, R.; Tripathi, S. Bromodomain and extra-terminal (BET) family proteins: New therapeutic targets in major diseases. J. Biosci., 2016, 41(2), 295-311.
[http://dx.doi.org/10.1007/s12038-016-9600-6] [PMID: 27240990]
Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W.B.; Fedorov, O.; Morse, E.M.; Keates, T.; Hickman, T.T.; Felletar, I.; Philpott, M.; Munro, S.; McKeown, M.R.; Wang, Y.; Christie, A.L.; West, N.; Cameron, M.J.; Schwartz, B.; Heightman, T.D.; La Thangue, N.; French, C.A.; Wiest, O.; Kung, A.L.; Knapp, S.; Bradner, J.E. Selective inhibition of BET bromodomains. Nature, 2010, 468(7327), 1067-1073.
[http://dx.doi.org/10.1038/nature09504] [PMID: 20871596]
Mirguet, O.; Lamotte, Y.; Donche, F.; Toum, J.; Gellibert, F.; Bouillot, A.; Gosmini, R.; Nguyen, V.L.; Delannée, D.; Seal, J.; Blandel, F.; Boullay, A.B.; Boursier, E.; Martin, S.; Brusq, J.M.; Krysa, G.; Riou, A.; Tellier, R.; Costaz, A.; Huet, P.; Dudit, Y.; Trottet, L.; Kirilovsky, J.; Nicodeme, E. From ApoA1 upregulation to BET family bromodomain inhibition: Discovery of I-BET151. Bioorg. Med. Chem. Lett., 2012, 22(8), 2963-2967.
[http://dx.doi.org/10.1016/j.bmcl.2012.01.125] [PMID: 22386529]
Seal, J.; Lamotte, Y.; Donche, F.; Bouillot, A.; Mirguet, O.; Gellibert, F.; Nicodeme, E.; Krysa, G.; Kirilovsky, J.; Beinke, S.; McCleary, S.; Rioja, I.; Bamborough, P.; Chung, C.W.; Gordon, L.; Lewis, T.; Walker, A.L.; Cutler, L.; Lugo, D.; Wilson, D.M.; Witherington, J.; Lee, K.; Prinjha, R.K. Identification of a novel series of BET family bromodomain inhibitors: Binding mode and profile of I-BET151 (GSK1210151A). Bioorg. Med. Chem. Lett., 2012, 22(8), 2968-2972.
[http://dx.doi.org/10.1016/j.bmcl.2012.02.041] [PMID: 22437115]
Dawson, M.A.; Prinjha, R.K.; Dittmann, A.; Giotopoulos, G.; Bantscheff, M.; Chan, W.I.; Robson, S.C.; Chung, C.W.; Hopf, C.; Savitski, M.M.; Huthmacher, C.; Gudgin, E.; Lugo, D.; Beinke, S.; Chapman, T.D.; Roberts, E.J.; Soden, P.E.; Auger, K.R.; Mirguet, O.; Doehner, K.; Delwel, R.; Burnett, A.K.; Jeffrey, P.; Drewes, G.; Lee, K.; Huntly, B.J.; Kouzarides, T. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature, 2011, 478(7370), 529-533.
[http://dx.doi.org/10.1038/nature10509] [PMID: 21964340]
Zhao, L.; Cao, D.; Chen, T.; Wang, Y.; Miao, Z.; Xu, Y.; Chen, W.; Wang, X.; Li, Y.; Du, Z.; Xiong, B.; Li, J.; Xu, C.; Zhang, N.; He, J.; Shen, J. Fragment-based drug discovery of 2-thiazolidinones as inhibitors of the histone reader BRD4 bromodomain. J. Med. Chem., 2013, 56(10), 3833-3851.
[http://dx.doi.org/10.1021/jm301793a] [PMID: 23530754]
Zhao, L.; Wang, Y.; Cao, D.; Chen, T.; Wang, Q.; Li, Y.; Xu, Y.; Zhang, N.; Wang, X.; Chen, D.; Chen, L.; Chen, Y.L.; Xia, G.; Shi, Z.; Liu, Y.C.; Lin, Y.; Miao, Z.; Shen, J.; Xiong, B. Fragment-based drug discovery of 2-thiazolidinones as BRD4 inhibitors: 2. Structure-based optimization. J. Med. Chem., 2015, 58(3), 1281-1297.
[http://dx.doi.org/10.1021/jm501504k] [PMID: 25559428]
Lucas, X.; Wohlwend, D.; Hügle, M.; Schmidtkunz, K.; Gerhardt, S.; Schüle, R.; Jung, M.; Einsle, O.; Günther, S. 4-Acyl pyrroles: Mimicking acetylated lysines in histone code reading. Angew. Chem. Int. Ed. Engl., 2013, 52(52), 14055-14059.
[http://dx.doi.org/10.1002/anie.201307652] [PMID: 24272870]
Siebel, A.L.; Trinh, S.K.; Formosa, M.F.; Mundra, P.A.; Natoli, A.K.; Reddy-Luthmoodoo, M.; Huynh, K.; Khan, A.A.; Carey, A.L.; van Hall, G.; Cobelli, C.; Dalla-Man, C.; Otvos, J.D.; Rye, K.A.; Johansson, J.; Gordon, A.; Wong, N.C.; Sviridov, D.; Barter, P.; Duffy, S.J.; Meikle, P.J.; Kingwell, B.A. Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomized controlled trial. Metabolism, 2016, 65(6), 904-914.
[http://dx.doi.org/10.1016/j.metabol.2016.03.002] [PMID: 27173469]
Jahagirdar, R.; Zhang, H.; Azhar, S.; Tobin, J.; Attwell, S.; Yu, R.; Wu, J.; McLure, K.G.; Hansen, H.C.; Wagner, G.S.; Young, P.R.; Srivastava, R.A.; Wong, N.C.; Johansson, J. A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice. Atherosclerosis, 2014, 236(1), 91-100.
[http://dx.doi.org/10.1016/j.atherosclerosis.2014.06.008] [PMID: 25016363]
Picaud, S.; Wells, C.; Felletar, I.; Brotherton, D.; Martin, S.; Savitsky, P.; Diez-Dacal, B.; Philpott, M.; Bountra, C.; Lingard, H.; Fedorov, O.; Müller, S.; Brennan, P.E.; Knapp, S.; Filippakopoulos, P. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc. Natl. Acad. Sci. USA, 2013, 110(49), 19754-19759.
[http://dx.doi.org/10.1073/pnas.1310658110] [PMID: 24248379]
Gilham, D.; Wasiak, S.; Tsujikawa, L.M.; Halliday, C.; Norek, K.; Patel, R.G.; Kulikowski, E.; Johansson, J.; Sweeney, M.; Wong, N.C.; Gordon, A.; McLure, K.; Young, P. RVX-208, a BET-inhibitor for treating atherosclerotic cardiovascular disease, raises ApoA-I/HDL and represses pathways that contribute to cardiovascular disease. Atherosclerosis, 2016, 247, 48-57.
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.01.036] [PMID: 26868508]
Gosmini, R.; Nguyen, V.L.; Toum, J.; Simon, C.; Brusq, J.M.; Krysa, G.; Mirguet, O.; Riou-Eymard, A.M.; Boursier, E.V.; Trottet, L.; Bamborough, P.; Clark, H.; Chung, C.W.; Cutler, L.; Demont, E.H.; Kaur, R.; Lewis, A.J.; Schilling, M.B.; Soden, P.E.; Taylor, S.; Walker, A.L.; Walker, M.D.; Prinjha, R.K.; Nicodème, E. The discovery of I-BET726 (GSK1324726A), a potent tetrahydroquinoline ApoA1 up-regulator and selective BET bromodomain inhibitor. J. Med. Chem., 2014, 57(19), 8111-8131.
[http://dx.doi.org/10.1021/jm5010539] [PMID: 25249180]
Fish, P.V.; Filippakopoulos, P.; Bish, G.; Brennan, P.E.; Bunnage, M.E.; Cook, A.S.; Federov, O.; Gerstenberger, B.S.; Jones, H.; Knapp, S.; Marsden, B.; Nocka, K.; Owen, D.R.; Philpott, M.; Picaud, S.; Primiano, M.J.; Ralph, M.J.; Sciammetta, N.; Trzupek, J.D. Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit. J. Med. Chem., 2012, 55(22), 9831-9837.
[http://dx.doi.org/10.1021/jm3010515] [PMID: 23095041]
Gallenkamp, D.; Gelato, K.A.; Haendler, B.; Weinmann, H. Bromodomains and their pharmacological inhibitors. ChemMedChem, 2014, 9(3), 438-464.
[http://dx.doi.org/10.1002/cmdc.201300434] [PMID: 24497428]
Theodoulou, N.H.; Tomkinson, N.C.; Prinjha, R.K.; Humphreys, P.G. Progress in the development of non-bet bromodomain chemical probes. ChemMedChem, 2016, 11(5), 477-487.
[http://dx.doi.org/10.1002/cmdc.201500540] [PMID: 26749027]
Ferguson, F.M.; Fedorov, O.; Chaikuad, A.; Philpott, M.; Muniz, J.R.; Felletar, I.; von Delft, F.; Heightman, T.; Knapp, S.; Abell, C.; Ciulli, A. Targeting low-druggability bromodomains: Fragment based screening and inhibitor design against the BAZ2B bromodomain. J. Med. Chem., 2013, 56(24), 10183-10187.
[http://dx.doi.org/10.1021/jm401582c] [PMID: 24304323]
Zengerle, M.; Chan, K.H.; Ciulli, A. Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol., 2015, 10(8), 1770-1777.
[http://dx.doi.org/10.1021/acschembio.5b00216] [PMID: 26035625]
Lu, J.; Qian, Y.; Altieri, M.; Dong, H.; Wang, J.; Raina, K.; Hines, J.; Winkler, J.D.; Crew, A.P.; Coleman, K.; Crews, C.M. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem. Biol., 2015, 22(6), 755-763.
[http://dx.doi.org/10.1016/j.chembiol.2015.05.009] [PMID: 26051217]

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Article Details

Year: 2020
Published on: 27 March, 2020
Page: [323 - 329]
Pages: 7
DOI: 10.2174/1570180816666190329223559

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