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Dual inhibitors of Janus kinase 2 and 3 (JAK2/3): designing by pharmacophore- and docking-based virtual screening approach

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Abstract

JAK2 and JAK3 are non-receptor protein tyrosine kinases implicated in B-cell- and T-cell-mediated diseases. Both enzymes work via different pathways but are involved in the pathogenesis of common lymphoid-derived diseases. Hence, targeting both Janus kinases together can be a potential strategy for the treatment of these diseases. In the present study, two separate pharmacophore-based 3D-QSAR models ADRR.92 (\(Q_{\mathrm{test}}^{2} 0.663, R^{2}_{\mathrm{train}} 0.849\), F value 219.3) for JAK2 and ADDRR.142 (\(Q^{2}_{\mathrm{test}}0.655, R_{\mathrm{train}}^{2}\) 0.869, F value 206.9) for JAK3 were developed. These models were employed for the screening of a PHASE database of approximately 1.5 million compounds; subsequently, the retrieved hits were screened employing docking simulations with JAK2 and JAK3 proteins. Finally, ADME properties of screened dual inhibitors displaying essential interactions with both proteins were calculated to filter candidates with poor pharmacokinetic profiles. These candidates could serve as novel therapeutic agents in the treatment of lymphoid-related diseases.

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References

  1. Heinrich PC, Behrmann I, Müller-Newen G, Schaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334:297–314

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Smith KA (1988) Interleukin-2: inception, impact, and implications. Science 240:1169–1176. doi:10.1126/science.3131876

    Article  CAS  PubMed  Google Scholar 

  3. Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A, Roifman CM (1996) Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379:645–648. doi:10.1038/379645a0

    Article  CAS  PubMed  Google Scholar 

  4. Kirken RA, Erwin RA, Taub D, Murphy WJ, Behbod F, Wang L, Pericle F, Farrar WL (1999) Tyrphostin AG-490 inhibits cytokine-mediated JAK3/STAT5a/b signal transduction and cellular proliferation of antigen-activated human T cells. J Leukoc Biol 65:891–899

    Google Scholar 

  5. Weinberg LR, Albom MS, Angeles TS, Breslin HJ, Gingrich DE, Huang Z, Lisko JG, Mason JL, Milkiewicz KL, Thieu TV (2011) 2,7-Pyrrolo[2,1-f][1,2,4]triazines as JAK2 inhibitors: modification of target structure to minimize reactive metabolite formation. Bioorg Med Chem Lett 21:7325–7330. doi:10.1016/j.bmcl.2011.10.032

    Article  CAS  PubMed  Google Scholar 

  6. Zificsak CA, Gingrich DE, Breslin HJ, Dunn DD, Milkiewicz KL, Theroff JP, Thieu TV, Underiner TL, Weinberg LR, Aimone LD (2012) Optimization of a novel kinase inhibitor scaffold for the dual inhibition of JAK2 and FAK kinases. Bioorg Med Chem Lett 22:133–137. doi:10.1016/j.bmcl.2011.11.049

    Article  CAS  PubMed  Google Scholar 

  7. Lim J, Taoka B, Otte RD, Spencer K, Dinsmore CJ, Altman MD, Chan G, Rosenstein C, Sharma S, Su H-P (2011) Discovery of 1-amino-5H-pyrido[4,3-b]indol-4-carboxamide inhibitors of Janus kinase 2 (JAK2) for the treatment of myeloproliferative disorders. J Med Chem 54:7334–7349. doi:10.1021/jm200909u

    Article  CAS  PubMed  Google Scholar 

  8. Siu T, Kozina ES, Jung J, Rosenstein C, Mathur A, Altman MD, Chan G, Xu L, Bachman E, Mo J-R (2010) The discovery of tricyclic pyridone JAK2 inhibitors. Part 1: hit to lead. Bioorg Med Chem Lett 20:7421–7425. doi:10.1016/j.bmcl.2010.10.031

    Article  CAS  PubMed  Google Scholar 

  9. Harikrishnan LS, Kamau MG, Wan H, Inghrim JA, Zimmermann K, Sang X, Mastalerz HA, Johnson WL, Zhang G, Lombardo LJ (2011) Pyrrolo[1,2-f]triazines as JAK2 inhibitors: achieving potency and selectivity for JAK2 over JAK3. Bioorg Med Chem Lett 21:1425–1428. doi:10.1016/j.bmcl.2011.01.022

    Article  CAS  PubMed  Google Scholar 

  10. Gerspacher M, Furet P, Pissot-Soldermann C, Gaul C, Holzer P, Vangrevelinghe E, Lang M, Erdmann D, Radimerski T, Regnier CH (2010) 2-Amino-aryl-7-aryl-benzoxazoles as potent, selective and orally available JAK2 inhibitors. Bioorg Med Chem Lett 20:1724–1727. doi:10.1016/j.bmcl.2010.01.069

    Article  CAS  PubMed  Google Scholar 

  11. Pissot-Soldermann C, Gerspacher M, Furet P, Gaul C, Holzer P, McCarthy C, Radimerski T, Regnier CH, Baffert F, Drueckes P (2010) Discovery and SAR of potent, orally available 2,8-diaryl-quinoxalines as a new class of JAK2 inhibitors. Bioorg Med Chem Lett 20:2609–2613. doi:10.1016/j.bmcl.2010.02.056

    Article  CAS  PubMed  Google Scholar 

  12. Malerich JP, Lam JS, Hart B, Fine RM, Klebansky B, Tanga MJ, D’Andrea A (2010) Diamino-1,2,4-triazole derivatives are selective inhibitors of TYK2 and JAK1 over JAK2 and JAK3. Bioorg Med Chem Lett 20:7454–7457. doi:10.1016/j.bmcl.2010.10.026

    Article  CAS  PubMed  Google Scholar 

  13. Schenkel LB, Huang X, Cheng A, Deak HL, Doherty E, Emkey R, Gu Y, Gunaydin H, Kim JL, Lee J (2011) Discovery of potent and highly selective thienopyridine Janus kinase 2 inhibitors. J Med Chem 54:8440–8450. doi:10.1021/jm200911r

    Article  CAS  PubMed  Google Scholar 

  14. Thoma G, Nuninger F, Falchetto R, Hermes E, Tavares GA, Vangrevelinghe E, Zerwes HG (2010) Identification of a potent Janus kinase 3 inhibitor with high selectivity within the Janus kinase family. J Med Chem 54:284–288. doi:10.1021/jm101157q

    Article  PubMed  Google Scholar 

  15. Burns CJ, Bourke DG, Andrau L, Bu X, Charman SA, Donohue AC, Fantino E, Farrugia M, Feutrill JT, Joffe M (2009) Phenylaminopyrimidines as inhibitors of Janus kinases (JAKs). Bioorg Med Chem Lett 19:5887–5892. doi:10.1016/j.bmcl.2009.08.071

    Article  CAS  PubMed  Google Scholar 

  16. Derenzini E, Lemoine M, Buglio D, Katayama H, Ji Y, Davis R, Sen S, Younes A (2011) The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma. Blood Cancer J 1:e46. doi:10.1038/bcj.2011.46

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Pardanani A, Lasho T, Smith G, Burns C, Fantino E, Tefferi A (2009) CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia 23:1441–1445. doi:10.1038/leu.2009.50

    Article  CAS  PubMed  Google Scholar 

  18. Quintás-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, Caulder E, Wen X, Li Y, Waeltz P, Rupar M, Burn T, Lo Y, Kelley J, Covington M, Shepard S, Rodgers JD, Haley P, Kantarjian H, Fridman JS, Verstovsek S (2010) Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 115:3109–3117. doi:10.1182/blood-2009-04-214957

    Article  PubMed Central  PubMed  Google Scholar 

  19. Wilson LJ, Malaviya R, Yang C, Argentieri R, Wang B, Chen X, Murray WV, Cavender D (2009) Synthetic staurosporines via a ring closing metathesis strategy as potent JAK3 inhibitors and modulators of allergic responses. Bioorg Med Chem Lett 19:3333–3338. doi:10.1016/j.bmcl.2009.04.039

    Article  CAS  PubMed  Google Scholar 

  20. Chen JJ, Thakur KD, Clark MP, Laughlin SK, George KM, Bookland RG, Davis JR, Cabrera EJ, Easwaran V, De B (2006) Development of pyrimidine-based inhibitors of Janus tyrosine kinase 3. Bioorg Med Chem Lett 16:5633–5638. doi:10.1016/j.bmcl.2006.08.022

    Article  CAS  PubMed  Google Scholar 

  21. Clark MP, George KM, Bookland RG, Chen J, Laughlin SK, Thakur KD, Lee W, Davis JR, Cabrera EJ, Brugel TA (2007) Development of new pyrrolopyrimidine-based inhibitors of Janus kinase 3 (JAK3). Bioorg Med Chem Lett 17:1250–1253. doi:10.1016/j.bmcl.2006.12.018

    Article  CAS  PubMed  Google Scholar 

  22. Adams C, Aldous DJ, Amendola S, Bamborough P, Bright C, Crowe S, Eastwood P, Fenton G, Foster M, Harrison TK (2003) Mapping the kinase domain of Janus kinase 3. Bioorg Med Chem Lett 13:3105–3110. doi:10.1016/S0960-894X(03)00657-7

    Article  CAS  PubMed  Google Scholar 

  23. Cole AG, Bohnstedt AC, Paradkar V, Kingsbury C, Quintero JG, Park H, Lu Y, You M, Neagu I, Diller DJ (2009) 2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors. Bioorg Med Chem Lett 19:6788–6792. doi:10.1016/j.bmcl.2009.09.080

    Article  CAS  PubMed  Google Scholar 

  24. Maestro, version 9.3, User Manual, Schrödinger, LLC, New York (2012)

  25. Ligprep, version 2.5, User Manual, Schrödinger, LLC, New York (2012)

  26. PHASE, version 3.4, Schrödinger, LLC, New York (2012)

  27. Dixon SL, Smondyrev AM, Knoll EH, Rao SN, Shaw DE, Friesner RA (2006) 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 20:647–671. doi:10.1007/s10822-006-9087-6

  28. Verma J, Khedkar VM, Coutinho EC (2010) 3D-QSAR in drug design: a review. Curr Top Med Chem 10:95–115. doi:10.2174/156802610790232260

    Article  CAS  PubMed  Google Scholar 

  29. Golbraikh A, Tropsha A (2002) Beware of q2!. J Mol Graph Model 20:269–276. doi:10.1016/S1093-3263(01)00123-1

    Article  CAS  PubMed  Google Scholar 

  30. Glide, version 5.8, User Manual, Schrödinger, LLC, New York (2012)

  31. Friesner RA, Banks J, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shaw DE, Shelley M, Perry JK, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749. doi:10.1021/jm0306430

    Article  CAS  PubMed  Google Scholar 

  32. QikProp, version 3.5, User Manual, Schrödinger, LLC, New York, NY (2012)

  33. Singh D, Karthikeyan M, Kirubakaran P, Nagamani S (2011) Pharmacophore filtering and 3D-QSAR in the discovery of new JAK2 inhibitors. J Mol Graph Model 30:186–197. doi:10.1016/j.jmgm.2011.07.004

    Article  Google Scholar 

  34. Baffert F, Régnier CH, De Pover A, Pissot-Soldermann C, Tavares GA, Blasco F, Brueggen J, Chène P, Drueckes P, Erdmann D (2010) Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805. Mol Cancer Ther 9:1945–1955. doi:10.1158/1535-7163

    Article  CAS  PubMed  Google Scholar 

  35. Antonysamy S, Hirst G, Park F, Sprengeler P, Stappenbeck F, Steensma R, Wilson M, Wong M (2009) Fragment-based discovery of JAK-2 inhibitors. Bioorg Med Chem Lett 19:279–282. doi:10.1016/j.bmcl.2008

    Article  CAS  PubMed  Google Scholar 

  36. Andraos R, Qian Z, Bonenfant D, Rubert J, Vangrevelinghe E, Scheufler C, Marque F, Régnier CH, De Pover A, Ryckelynck H (2012) Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent. Cancer Discov 2:512–523. doi:10.1158/2159-8290

    Article  CAS  PubMed  Google Scholar 

  37. Bandaranayake RM, Ungureanu D, Shan Y, Shaw DE, Silvennoinen O, Hubbard SR (2012) Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F. Nat Struct Mol Biol 19:754–759. doi:10.1038/nsmb.2348

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Boggon TJ, Li Y, Manley PW, Eck MJ (2005) Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog. Blood 106:996–1002. doi:10.1182/blood-2005-02-0707

    Google Scholar 

  39. Soth M, Hermann JC, Yee C, Alam M, Barnett JW, Berry P, Browner MF, Frank K, Frauchiger S, Harris S (2012) 3-Amido pyrrolopyrazine JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in cellular and in vivo models. J Med Chem 56:345–356. doi:10.1021/jm301646k

    Google Scholar 

  40. Chrencik JE, Patny A, Leung IK, Korniski B, Emmons TL, Hall T, Weinberg RA, Gormley JA, Williams JM, Day JE (2010) Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J Mol Biol 400:413–433. doi:10.1016/j.jmb.2010.05.020

    Google Scholar 

  41. Dymock BW, See CS (2013) Inhibitors of JAK2 and JAK3: an update on the patent literature 2010–2012. Expert Opin Ther Pat 23:449–501. doi:10.1517/13543776.2013.765862

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Authors would like to thank Dr. Ravikumar Muttineni (Application Scientist), Er. Anirban Banerjee (IT Consultant), and Mr. Raghu Rangaswamy from Schrödinger, Bangalore, for their constant scientific and technical support to handle Schrödinger software and work smoothly. Authors also thank University Grant Commission, New Delhi, for providing the financial support; Grant No. 37-324/2009(SR).

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Authors and Affiliations

  1. Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala , 147002, Punjab, India

    Haneesh Jasuja, Navriti Chadha, Maninder Kaur & Om Silakari

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  1. Haneesh Jasuja
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  2. Navriti Chadha
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  3. Maninder Kaur
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  4. Om Silakari
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Correspondence to Om Silakari.

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Jasuja, H., Chadha, N., Kaur, M. et al. Dual inhibitors of Janus kinase 2 and 3 (JAK2/3): designing by pharmacophore- and docking-based virtual screening approach. Mol Divers 18, 253–267 (2014). https://doi.org/10.1007/s11030-013-9497-z

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  • DOI: https://doi.org/10.1007/s11030-013-9497-z

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