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Structural insights for design of potent spleen tyrosine kinase inhibitors from crystallographic analysis of three inhibitor complexes.

Villaseñor AG, Kondru R, Ho H, Wang S, Papp E, Shaw D, Barnett JW, Browner MF, Kuglstatter A
Chem Biol Drug Des 73 466-70 (2009)
Related entries: 3fqe, 3fqs

Cited: 25 times
EuropePMC logo PMID: 19220318

Abstract

Spleen tyrosine kinase is considered an attractive drug target for the treatment of allergic and antibody mediated autoimmune diseases. We have determined the co-crystal structures of spleen tyrosine kinase complexed with three known inhibitors: YM193306, a 7-azaindole derivative and R406. The cis-cyclohexyldiamino moiety of YM193306 is forming four hydrophobically shielded polar interactions with the spleen tyrosine kinase protein and is therefore crucial for the high potency of this inhibitor. Its primary amino group is inducing a conformational change of the spleen tyrosine kinase DFG Asp side chain. The crystal structure of the 7-azaindole derivative bound to spleen tyrosine kinase is the first demonstration of a 2-substituted 7-azaindole bound to a protein kinase. Its indole-amide substituent is tightly packed between the N- and C-terminal kinase lobes. The co-crystal structure of the spleen tyrosine kinase-R406 complex shows two main differences to the previously reported structure of spleen tyrosine kinase soaked with R406: (i) the side chain of the highly conserved Lys is disordered and not forming a hydrogen bond to R406 and (ii) the DFG Asp side chain is pointing away from and not towards R406. The novel protein-ligand interactions and protein conformational changes revealed in these structures guide the rational design and structure-based optimization of second-generation spleen tyrosine kinase inhibitors.

Reviews - 3fqh mentioned but not cited (1)

  1. The azaindole framework in the design of kinase inhibitors. Mérour JY, Buron F, Plé K, Bonnet P, Routier S. Molecules 19 19935-19979 (2014)

Articles - 3fqh mentioned but not cited (1)

  1. Fragment-based screening maps inhibitor interactions in the ATP-binding site of checkpoint kinase 2. Silva-Santisteban MC, Westwood IM, Boxall K, Brown N, Peacock S, McAndrew C, Barrie E, Richards M, Mirza A, Oliver AW, Burke R, Hoelder S, Jones K, Aherne GW, Blagg J, Collins I, Garrett MD, van Montfort RL. PLoS One 8 e65689 (2013)


Reviews citing this publication (8)

  1. The Src, Syk, and Tec family kinases: distinct types of molecular switches. Bradshaw JM. Cell Signal 22 1175-1184 (2010)
  2. Tyrosine kinase inhibitors as potential drugs for B-cell lymphoid malignancies and autoimmune disorders. Robak T, Robak E. Expert Opin Investig Drugs 21 921-947 (2012)
  3. Therapeutic prospect of Syk inhibitors. Ruzza P, Biondi B, Calderan A. Expert Opin Ther Pat 19 1361-1376 (2009)
  4. Spleen tyrosine kinase as a molecular target for treatment of leukemias and lymphomas. Uckun FM, Qazi S. Expert Rev Anticancer Ther 10 1407-1418 (2010)
  5. Spleen tyrosine kinase inhibitors: a review of the patent literature 2010 - 2013. Norman P. Expert Opin Ther Pat 24 573-595 (2014)
  6. Bruton's TK inhibitors: structural insights and evolution of clinical candidates. Xing L, Huang A. Future Med Chem 6 675-695 (2014)
  7. Small-molecule inhibitors of spleen tyrosine kinase as therapeutic agents for immune disorders: will promise meet expectations? Lucas MC, Tan SL. Future Med Chem 6 1811-1827 (2014)
  8. Clinical Pharmacokinetics and Pharmacodynamics of Fostamatinib and Its Active Moiety R406. Matsukane R, Suetsugu K, Hirota T, Ieiri I. Clin Pharmacokinet 61 955-972 (2022)

Articles citing this publication (15)

  1. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Quiroga MP, Balakrishnan K, Kurtova AV, Sivina M, Keating MJ, Wierda WG, Gandhi V, Burger JA. Blood 114 1029-1037 (2009)
  2. Structural and biophysical characterization of the Syk activation switch. Grädler U, Schwarz D, Dresing V, Musil D, Bomke J, Frech M, Greiner H, Jäkel S, Rysiok T, Müller-Pompalla D, Wegener A. J Mol Biol 425 309-333 (2013)
  3. Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implications for SYK inhibitors in autoimmune disease therapy. Liao C, Hsu J, Kim Y, Hu DQ, Xu D, Zhang J, Pashine A, Menke J, Whittard T, Romero N, Truitt T, Slade M, Lukacs C, Hermann J, Zhou M, Lucas M, Narula S, DeMartino J, Tan SL. Arthritis Res Ther 15 R146 (2013)
  4. Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures. Kuglstatter A, Wong A, Tsing S, Lee SW, Lou Y, Villaseñor AG, Bradshaw JM, Shaw D, Barnett JW, Browner MF. Protein Sci 20 428-436 (2011)
  5. Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice. Wang L, Aschenbrenner D, Zeng Z, Cao X, Mayr D, Mehta M, Capitani M, Warner N, Pan J, Wang L, Li Q, Zuo T, Cohen-Kedar S, Lu J, Ardy RC, Mulder DJ, Dissanayake D, Peng K, Huang Z, Li X, Wang Y, Wang X, Li S, Bullers S, Gammage AN, Warnatz K, Schiefer AI, Krivan G, Goda V, Kahr WHA, Lemaire M, Genomics England Research Consortium, Lu CY, Siddiqui I, Surette MG, Kotlarz D, Engelhardt KR, Griffin HR, Rottapel R, Decaluwe H, Laxer RM, Proietti M, Hambleton S, Elcombe S, Guo CH, Grimbacher B, Dotan I, Ng SC, Freeman SA, Snapper SB, Klein C, Boztug K, Huang Y, Li D, Uhlig HH, Muise AM. Nat Genet 53 500-510 (2021)
  6. Targeting kinases for the treatment of inflammatory diseases. Müller S, Knapp S. Expert Opin Drug Discov 5 867-881 (2010)
  7. Syk inhibitors with high potency in presence of blood. Thoma G, Blanz J, Bühlmayer P, Drückes P, Kittelmann M, Smith AB, van Eis M, Vangrevelinghe E, Zerwes HG, Che JJ, He X, Jin Y, Lee CC, Michellys PY, Uno T, Liu H. Bioorg Med Chem Lett 24 2278-2282 (2014)
  8. LEADOPT: an automatic tool for structure-based lead optimization, and its application in structural optimizations of VEGFR2 and SYK inhibitors. Li GB, Ji S, Yang LL, Zhang RJ, Chen K, Zhong L, Ma S, Yang SY. Eur J Med Chem 93 523-538 (2015)
  9. Biophysical and mechanistic insights into novel allosteric inhibitor of spleen tyrosine kinase. Hall J, Aulabaugh A, Rajamohan F, Liu S, Kaila N, Wan ZK, Ryan M, Magyar R, Qiu X. J Biol Chem 287 7717-7727 (2012)
  10. A combined experimental and computational study of Vam3, a derivative of resveratrol, and Syk interaction. Jiang M, Liu R, Chen Y, Zheng Q, Fan S, Liu P. Int J Mol Sci 15 17188-17203 (2014)
  11. Syk Inhibitors: New Computational Insights into Their Intraerythrocytic Action in Plasmodium falciparum Malaria. Marchetti G, Dessì A, Dallocchio R, Tsamesidis I, Pau MC, Turrini FM, Pantaleo A. Int J Mol Sci 21 E7009 (2020)
  12. Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization. Ellis JM, Altman MD, Cash B, Haidle AM, Kubiak RL, Maddess ML, Yan Y, Northrup AB. ACS Med Chem Lett 7 1151-1155 (2016)
  13. Identification of pyrazolopyridine derivatives as novel spleen tyrosine kinase inhibitors. Huang Y, Li Y, Dong G, Zhang W, Liu N, Sheng C. Arch Pharm (Weinheim) (2018)
  14. Synthesis and optimization of furano[3,2-d]pyrimidines as selective spleen tyrosine kinase (Syk) inhibitors. Hoemann M, Wilson N, Argiriadi M, Banach D, Burchat A, Calderwood D, Clapham B, Cox P, Duignan DB, Konopacki D, Somal G, Vasudevan A. Bioorg Med Chem Lett 26 5562-5567 (2016)
  15. X-ray crystal structure, vibrational spectra and DFT calculations of 3-chloro-7-azaindole: a case of dual N-H⋯N hydrogen bonds in dimers. Morzyk-Ociepa B, Dysz K, Turowska-Tyrk I, Michalska D. Spectrochim Acta A Mol Biomol Spectrosc 136 Pt B 405-415 (2015)


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