Identification of new dual spleen tyrosine kinase (Syk) and phosphoionositide-3-kinase δ (PI3Kδ) inhibitors using ligand and structure-based integrated ideal pharmacophore models

References

• J.L. Browning, B cells move to centre stage: Novel opportunities for autoimmune disease treatment, Nat. Rev. Drug Discov. 5 (2006), pp. 564–576.
   PubMed Web of Science ®Google Scholar
• K.D. Puri, J.A. Di Paolo, and M.R. Gold, B-cell receptor signaling inhibitors for treatment of autoimmune inflammatory diseases and B-cell malignancies, Int. Rev. Immunol. 32 (2013), pp. 397–427.
   PubMed Web of Science ®Google Scholar
• N.A. Mitchison and L.R. Wedderburn, B cells in autoimmunity, PNAS 97 (2000), pp. 8750–8751.
   PubMed Web of Science ®Google Scholar
• N. Fowler and E. Davis, Targeting B-cell receptor signaling: Changing the paradigm, ASH Education Program Book 1 (2013), pp. 553–560.
   Google Scholar
• V. Seda and M. Marek, B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells, Eur. J. Haematol. 94 (2015), pp. 193–205.
   PubMed Web of Science ®Google Scholar
• R.J. Cornall, A.M. Cheng, T. Pawson, and C.C. Goodnow, Role of Syk in B-cell development and antigen-receptor signaling, PNAS 97 (2000), pp. 1713–1718.
   PubMed Web of Science ®Google Scholar
• M. Werner, E. Hobeika, and H. Jumaa, Role of PI3K in the generation and survival of B cells, Immunol. Rev. 37 (2010), pp. 55–71.
   Google Scholar
• M.E. Weinblatt, M.C. Genovese, M. Ho, S. Hollis, K. Rosiak-Jedrychowicz, A. Kavanaugh, D.S. Millson, G. Leon, M. Wang, and D. van der Heijde, Effects of fostamatinib, an oral spleen tyrosine kinase inhibitor, in rheumatoid arthritis patients with an inadequate response to methotrexate: Results from a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, Arthritis Rheumatol. 66 (2014), pp. 3255–3264.
   PubMed Web of Science ®Google Scholar
• https://www.clinicaltrials.gov/ct2/show/NCT02004522?term=NCT02004522&rank=1.
   Google Scholar
• P. Csermely, V. Agoston, and S. Pongor, The efficiency of multi-target drugs: The network approach might help drug design, Trends Pharmacol. Sci. 26 (2005), pp. 178–182.
   PubMed Web of Science ®Google Scholar
• S. Frantz, Drug discovery: Playing dirty, Nature 437 (2005), pp. 942–943.
   PubMed Web of Science ®Google Scholar
• H. Kitano, A robustness-based approach to systems-oriented drug design, Nat. Rev. Drug Discov. 5 (2007), pp. 202–210.
   Web of Science ®Google Scholar
• G.R. Zimmermann, J. Lehar, and C.T. Keith, Multi-target therapeutics: When the whole is greater than the sum of the parts, Drug Discov. Today 12 (2007), pp. 34–42.
   PubMed Web of Science ®Google Scholar
• C.L. Cywin, B.P. Zhao, D.W. McNeil, M. Hrapchak, A.S. Prokopowicz, D.R. Goldberg, T.M. Morwick, A. Gao, S. Jakes, M. Kashem, R.L. Magolda, R.M. Soll, M.R. Player, M.A. Bobko, J. Rinker, R.L. DesJarlais, and M.P. Winters, Discovery and SAR of novel [1, 6] naphthyridines as potent inhibitors of spleen tyrosine kinase (SYK), Bioorg. Med. Chem. Lett. 13 (2002), pp. 1415–1418.
   Web of Science ®Google Scholar
• A. Hirabayashi, H. Mukaiyama, H. Kobayashi, H. Shiohara, S. Nakayama, M. Ozawa, E. Tsuji, K. Miyazawa, K. Misawa, H. Ohnota, and M. Isaji, Structure-activity relationship studies of imidazo[1,2-c]pyrimidine derivatives as potent and orally effective Syk family kinases inhibitors, Bioorg. Med. Chem. Lett. 16(20) (2008), pp. 9247–9260.
   Web of Science ®Google Scholar
• H. Hisamichi, R. Naito, A. Toyoshima, N. Kawano, A. Ichikawa, A. Orita, M. Orita, N. Hamada, M. Takeuchi, M. Ohta, and S. Tsukamoto, Synthetic studies on novel Syk inhibitors. Part 1: Synthesis and structure-activity relationships of pyrimidine-5-carboxamide derivatives, Bioorg. Med. Chem. Lett. 13 (2005), pp. 4936–4951.
   Web of Science ®Google Scholar
• A. Hirabayashi, H. Mukaiyama, H. Kobayashi, H. Shiohara, S. Nakayama, M. Ozawa, K. Miyazawa, K. Misawa, H. Ohnota, and M. Isaji, A novel Syk family kinase inhibitor: Design, synthesis, and structure-activity relationship of 1,2,4-triazolo[4,3-c]pyrimidine and 1,2,4-triazolo[1,5-c]pyrimidine derivatives, Bioorg. Med. Chem. Lett. 16 (2008), pp. 7347–7357.
   Web of Science ®Google Scholar
• J.Y. Lai, P.J. Cox, R. Patel, S. Sadiq, D.J. Aldous, S. Thurairatnam, K. Smith, D. Wheeler, S. Jagpal, S. Parveen, G. Fenton, T.K. Harrison, C. McCarthy, and P.J. Bamborough, Potent small molecule inhibitors of spleen tyrosine kinase (Syk), Bioorg. Med. Chem. Lett. 13 (2003), pp. 3111–3114.
   PubMed Web of Science ®Google Scholar
• M. Castillo, P. Forns, M. Erra, M. Mir, M. López, M. Maldonado, A. Orellana, C. Carreño, I. Ramis, M. Miralpeix, and B. Vidal, Highly potent aminopyridines as Syk kinase inhibitors, Bioorg. Med. Chem. Lett. 22 (2012), pp. 5419–5423.
   PubMed Web of Science ®Google Scholar
• P. Forns, C. Esteve, L. Taboada, J.A. Alonso, A. Orellana, M. Maldonado, C. Carreño, I. Ramis, M. López, M. Miralpeix, and B. Vidal, Pyrazine-based Syk kinase inhibitors, Bioorg. Med. Chem. Lett. 22 (2012), pp. 2784–2788.
   PubMed Web of Science ®Google Scholar
• J. Liddle, F.L. Atkinson, M.D. Barker, P.S. Carter, N.R. Curtis, R.P. Davis, C. Douault, M.C. Dickson, D. Elwes, N.S. Garton, M. Gray, T.G. Hayhow, C.I. Hobbs, E. Jones, S. Leach, K. Leavens, H.D. Lewis, S. McCleary, M. Neu, V.K. Patel, A.G. Preston, C. Ramirez-Molina, T.J. Shipley, P.A. Skone, N. Smithers, D.O. Somers, A.L. Walker, R.J. Watson, and G.G. Weingarten, Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor, Bioorg. Med. Chem. Lett. 21 (2011), pp. 6188–6194.
   PubMed Web of Science ®Google Scholar
• R. Alexander, A. Balasundaram, M. Batchelor, D. Brookings, K. Crépy, T. Crabbe, M.F. Deltent, F. Driessens, A. Gill, S. Harris, G. Hutchinson, C. Kulisa, M. Merriman, P. Mistry, T. Parton, J. Turner, I. Whitcombe, and S. Wright, 4-(1,3-Thiazol-2-yl)morpholine derivatives as inhibitors of phosphoinositide 3-kinase, Bioorg. Med. Chem. Lett. 18 (2008), pp. 4316–4320.
   PubMed Web of Science ®Google Scholar
• R. Frédérick, C. Mawson, J.D. Kendall, C. Chaussade, G.W. Rewcastle, P.R. Shepherd, and W.A. Denny, Phosphoinositide-3-kinase (PI3K) inhibitors: Identification of new scaffolds using virtual screening, Bioorg. Med. Chem. Lett. 19 (2009), pp. 5842–5847.
   PubMed Web of Science ®Google Scholar
• R.M. Sanchez, K. Erhard, M.A. Hardwicke, H. Lin, J. McSurdy-Freed, R. Plant, K. Raha, C.M. Rominger, M.D. Schaber, M.D. Spengler, M.L. Moore, H. Yu, J.I. Luengo, R. Tedesco, and R.A. Rivero, Synthesis and structure-activity relationships of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones as novel series of potent β isoform selective phosphatidylinositol 3-kinase inhibitors, Bioorg. Med. Chem. Lett. 22 (2012), pp. 3198–3202.
   PubMed Web of Science ®Google Scholar
• D.P. Sutherlin, S. Baker, A. Bisconte, P.M. Blaney, A. Brown, B.K. Chan, D. Chantry, G. Castanedo, P. DePledge, P. Goldsmith, D.M. Goldstein, T. Hancox, J. Kaur, D. Knowles, R. Kondru, J. Lesnick, M.C. Lucas, C. Lewis, J. Murray, A.J. Nadin, J. Nonomiya, J. Pang, N. Pegg, S. Price, K. Reif, B.S. Safina, L. Salphati, S. Staben, E.M. Seward, S. Shuttleworth, S. Sohal, Z.K. Sweeney, M. Ultsch, B. Waszkowycz, and B. Wei, Potent and selective inhibitors of PI3Kδ: Obtaining isoform selectivity from the affinity pocket and tryptophan shelf, Bioorg. Med. Chem. Lett. 22 (2012), pp. 4296–4302.
   PubMed Web of Science ®Google Scholar
• K. Ellard, M. Sunose, K. Bell, N. Ramsden, G. Bergamini, and G. Neubauer, Discovery of novel PI3Kγ/δ inhibitors as potential agents for inflammation, Bioorg. Med. Chem. Lett. 22 (2012), pp. 4546–4549.
   PubMed Web of Science ®Google Scholar
• B. Barlaam, S. Cosulich, S. Degorce, M. Fitzek, F. Giordanetto, S. Green, T. Inghardt, L. Hennequin, U. Hancox, C. Lambert-van der Brempt, R. Morgentin, S. Pass, P. Plé, T. Saleh, and L. Ward, Discovery of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumours, Bioorg. Med. Chem. Lett. 24 (2014), pp. 3928–3935.
   PubMed Web of Science ®Google Scholar
• J.D. Kendall, G.W. Rewcastle, R. Frederick, C. Mawson, W.A. Denny, E.S. Marshall, B.C. Baguley, C. Chaussade, S.P. Jackson, and P.R. Shepherd, Synthesis, biological evaluation and molecular modelling of sulfonhydrazides as selective PI3K p110alpha inhibitors, Bioorg. Med. Chem. 15 (2007), pp. 7677–7687.
   PubMed Web of Science ®Google Scholar
• R.R. Kuang, F. Qian, Z. Li, and D.Z.J. Wei, Study on improving the selectivity of compounds that inhibit two PI3Ks (gamma and delta), J. Mol. Model. 12 (2006), pp. 445–452.
   PubMed Web of Science ®Google Scholar
• F. Gonzalez-Lopez de Turiso, Y. Shin, M. Brown, M. Cardozo, Y. Chen, D. Fong, X. Hao, X. He, K. Henne, Y.L. Hu, M.G. Johnson, T. Kohn, J. Lohman, H.J. McBride, L.R. McGee, J.C. Medina, D. Metz, K. Miner, D. Mohn, V. Pattaropong, J. Seganish, J.L. Simard, S. Wannberg, D.A. Whittington, G. Yu, and T.D. Cushing, Discovery and in vivo evaluation of dual PI3Kβ/δ inhibitors, J. Med. Chem. 55 (2012), pp. 7667–7685.
   PubMed Web of Science ®Google Scholar
• J.M. Murray, Z.K. Sweeney, B.K. Chan, M. Balazs, E. Bradley, G. Castanedo, C. Chabot, D. Chantry, M. Flagella, D.M. Goldstein, R. Kondru, J. Lesnick, J. Li, M.C. Lucas, J. Nonomiya, J. Pang, S. Price, L. Salphati, B. Safina, P.P. Savy, E.M. Seward, M. Ultsch, and D.P. Sutherlin, Potent and highly selective benzimidazole inhibitors of PI3-kinase delta, J. Med. Chem. 55 (2012), pp. 7686–7695.
   PubMed Web of Science ®Google Scholar
• B.S. Safina, S. Baker, M. Baumgardner, P.M. Blaney, B.K. Chan, Y.H. Chen, M.W. Cartwright, G. Castanedo, C. Chabot, A.J. Cheguillaume, P. Goldsmith, D.M. Goldstein, B. Goyal, T. Hancox, R.K. Handa, P.S. Iyer, J. Kaur, R. Kondru, J.R. Kenny, S.L. Krintel, J. Li, J. Lesnick, M.C. Lucas, C. Lewis, S. Mukadam, J. Murray, A.J. Nadin, J. Nonomiya, F. Padilla, W.S. Palmer, J. Pang, N. Pegg, and S. Price, K, Reif, L. Salphati, P.A. Savy, E.M. Seward, S. Shuttleworth, S. Sohal, Z.K. Sweeney, S. Tay, P. Tivitmahaisoon, B. Waszkowycz, B. Wei, Q. Yue, C. Zhang, and D.P. Sutherlin DP, Discovery of novel PI3-kinase δ specific inhibitors for the treatment of rheumatoid arthritis: Taming CYP3A4 time-dependent inhibition, J. Med. Chem. 55 (2010), pp. 5887–5900.
   Web of Science ®Google Scholar
• Maestro, version 9.3, User Manual, Schrödinger, LLC, New York, 2012.
   Google Scholar
• Ligprep, version 2.5, User Manual, Schrödinger, LLC, New York, 2012.
   Google Scholar
• http://www.rcsb.org/pdb/home/home.do.
   Google Scholar
• G.M. Sastry, M. Adzhigirey, T. Day, R. Annabhimoju, and W. Sherman, Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments, J. Comput. Aided Mol. Des. 27 (2013), pp. 221–234.
   PubMed Web of Science ®Google Scholar
• Glide, version 5.8, User Manual, Schrödinger, LLC, New York, 2012.
   Google Scholar
• R.A. Friesner, J.L. Banks, R.B. Murphy, T.A. Halgren, J.J. Klicic, D.T. Mainz, M.P. Repasky, E.H. Knoll, D.E. Shaw, M. Shelley, J.K. Perry, P. Francis, and Glide Shenkin, A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy, J. Med. Chem. 47 (2004), pp. 1739–1749.
   PubMed Web of Science ®Google Scholar
• PHASE, version 3.4, Schrödinger, LLC, New York, 2012.
   Google Scholar
• S.L. Dixon, A.M. Smondyrev, E.H. Knoll, S.N. Rao, D.E. Shaw, and R.A. Friesner, PHASE: A new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening. 1. Methodology and preliminary results, J. Comput. Aided Mol. Des. 20 (2006), pp. 647–671.
   PubMed Web of Science ®Google Scholar
• J. Verma, V.M. Khedkar, and E.C. Coutinho, 3D-QSAR in drug design: A review, Curr. Top. Med. Chem. 10 (2010), pp. 95–115.
   PubMed Web of Science ®Google Scholar
• A. Golbraikh and A. Tropsha, Beware of q2!, J. Mol. Graph. Model. 20 (2002), pp. 269–276.
   PubMed Web of Science ®Google Scholar
• M. Kaur, A. Kumari, M.S. Bahia, and O. Silakari, Designing of new multi-targeted inhibitors of spleen tyrosine kinase (Syk) and zeta-associated protein of 70 kDa (ZAP-70) using hierarchical virtual screening protocol, J. Mol. Graph. Model. 39 (2013), pp. 165–175.
   PubMed Web of Science ®Google Scholar
• S. Weaver and M.P. Gleeson, The importance of the domain of applicability in QSAR modeling, J. Mol. Graph. Model. 26 (2008), pp. 1315–1326.
   PubMed Web of Science ®Google Scholar
• V.D. Mouchlis, G. Melagraki, and T. Mavromoustakos, Kollias, and A. Afantitis, Molecular modeling on pyrimidine-urea inhibitors of TNF-α production: An integrated approach using a combination of molecular docking, classification techniques, and 3D-QSAR CoMSIA, J. Chem. Inf. Model. 52 (2012), pp. 711–723.
   PubMed Web of Science ®Google Scholar
• R.D. Cramer, J.D. Bunce, D.E. Patterson, and I.E. Frank, Crossvalidation, bootstrapping, and partial least squares compared with multiple regression in conventional QSAR studies, Quant. Struct. Act. Relat. 7 (1988), pp. 18–25.
   Google Scholar
• N.K. Salam, R. Nuti, and W. Sherman, Novel method for generating structure-based pharmacophores using energetic analysis, J. Chem. Inf. Model. 49 (2009), pp. 2356–2368.
   PubMed Web of Science ®Google Scholar
• B.V. Kumar, R. Kotla, R. Buddiga, J. Roy, S.S. Singh, R. Gundla, M. Ravikumar, and J.A. Sarma, Ligand-based and structure-based approaches in identifying ideal pharmacophore against c-Jun N-terminal kinase-3, J. Mol. Model. 17 (2011), pp. 151–163.
   PubMed Web of Science ®Google Scholar
• A.S. Reddy, S.P. Pati, P.P. Kumar, H.N. Pradeep, and G.N. Sastry, Virtual screening in drug discovery – a computational perspective, Curr. Protein Pept. Sci. 8 (2007), pp. 329–351.
   PubMed Web of Science ®Google Scholar
• S.H. Lu, J.W. Wu, H.L. Liu, J.H. Zhao, K.T. Liu, C.K. Chuang, H.Y. Lin, W.B. Tsai, and Y. Ho, The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies, J. Biomed. Sci. 18 (2011), p. b22.
   PubMed Web of Science ®Google Scholar
• A. Bender and R.C. Glen, A discussion of measures of enrichment in virtual screening: Comparing the information content of descriptors with increasing levels of sophistication, J. Chem. Inf. Model. 45 (2005), pp. 1369–1375.
   PubMed Web of Science ®Google Scholar
• QikProp, version 3.5; Schrödinger, LLC, New York, NY, 2012.
   Google Scholar
• Prime, version 3.1, Schrödinger, LLC, New York, NY, 2012.
   Google Scholar
• M.C. Lucas, D.M. Goldstein, J.C. Hermann, A. Kuglstatter, W. Liu, K.C. Luk, F. Padilla, M. Slade, A.G. Villaseñor, J. Wanner, W. Xie, X. Zhang, and C. Liao, Rational design of highly selective spleen tyrosine kinase inhibitors, J. Med. Chem. 55 (2012), pp. 10414–10423.
   PubMed Web of Science ®Google Scholar
• S. Atwell, J.M. Adams, J. Badger, M.D. Buchanan, I.K. Feil, K.J. Froning, X. Gao, J. Hendle, K. Keegan, B.C. Leon, H.J. Müller-Dieckmann, V.L. Nienaber, B.W. Noland, K. Post, K.R. Rajashankar, A. Ramos, M. Russell, S.K. Burley, and S.G. Buchanan, A novel mode of Gleevec binding is revealed by the structure of spleen tyrosine kinase, J. Biol. Chem. 279 (2004), pp. 55827–55832.
   PubMed Web of Science ®Google Scholar
• G. Thoma, J. Blanz, P. Bühlmayer, P. Drückes, M. Kittelmann, A.B. Smith, M. van Eis, E. Vangrevelinghe, H.G. Zerwes, J.J. Che, X. He, Y. Jin, C.C. Lee, P.Y. Michellys, T. Uno, and H. Liu, Syk inhibitors with high potency in presence of blood, Bioorg. Med. Chem. Lett. 24 (2014), pp. 2278–2282.
   PubMed Web of Science ®Google Scholar
• G. Kozlov, R. Vinaik, and K. Gehring, Triosephosphate isomerase is a common crystallization contaminant of soluble His-tagged proteins produced in Escherichia coli, Acta Crystallogr, Sect. F. Struct. Biol. Cryst. Commun. 69 (2013), pp. 499–502.
   PubMedGoogle Scholar
• L.R. McLean, Y. Zhang, N. Zaidi, X. Bi, R. Wang, R. Dharanipragada, J.G. Jurcak, T.A. Gillespy, Z. Zhao, K.Y. Musick, Y.M. Choi, M. Barrague, J. Peppard, M. Smicker, M. Duguid, A. Parkar, J. Fordham, and D. Kominos, X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase, Bioorg. Med. Chem. Lett. 22 (2012), pp. 3296–3300.
   PubMed Web of Science ®Google Scholar
• K.S. Currie, J.E. Kropf, T. Lee, P. Blomgren, J. Xu, Z. Zhao, S. Gallion, J.A. Whitney, D. Maclin, E.B. Lansdon, P. Maciejewski, A.M. Rossi, H. Rong, J. Macaluso, J. Barbosa, J.A. Di Paolo, and S.A. Mitchell, Discovery of GS-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase, J. Med. Chem. 57 (2014), pp. 3856–3873.
   PubMed Web of Science ®Google Scholar
• A.T. Berndt, S. Miller, O. Williams, D.D. Le, B.T. Houseman, J.I. Pacold, F. Gorrec, W.C. Hon, Y. Liu, C. Rommel, P. Gaillard, T. Rückle, M.K. Schwarz, K.M. Shokat, J.P. Shaw, and R.L. Williams, The p110 delta structure: Mechanisms for selectivity and potency of new PI(3)K inhibitors, Nat. Chem. Biol. 6 (2010), pp. 117–124.
   PubMed Web of Science ®Google Scholar