spleen associated tyrosine kinase | Syk family | IUPHAR/BPS Guide to PHARMACOLOGY

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spleen associated tyrosine kinase

target has curated data in GtoImmuPdb

Target id: 2230

Nomenclature: spleen associated tyrosine kinase

Abbreviated Name: Syk

Family: Syk family

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 635 9q22 SYK spleen associated tyrosine kinase
Mouse - 629 13 B-C2 Syk spleen tyrosine kinase
Rat - 629 17 p14 Syk spleen associated tyrosine kinase
Previous and Unofficial Names
p72syk | Sykb
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Structural and biophysical characterization of the Syk activation switch.
PDB Id:  4FL2
Resolution:  2.19Å
Species:  Human
References:  12
Image of receptor 3D structure from RCSB PDB
Description:  CRYSTAL STRUCTURE OF SPLEEN TYROSINE KINASE (SYK) IN COMPLEX WITH A 2-(PHENOXYMETHYL)PYRIDINE INHIBITOR (GSK26462640.
PDB Id:  6HM7
Ligand:  GSK2646264
Resolution:  1.64Å
Species:  Human
References:  3
Enzyme Reaction
EC Number: 2.7.10.2

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
tamatinib Hs Inhibition 7.7 pKd 9
pKd 7.7 (Kd 1.9x10-8 M) [9]
mivavotinib Hs Inhibition 8.0 pEC50 16
pEC50 8.0 (EC50 9.8x10-9 M) [16]
Description: Cellular potency
TAS05567 Hs Inhibition 9.4 pIC50 13
pIC50 9.4 (IC50 3.7x10-10 M) [13]
P505-15 Hs Inhibition 9.0 pIC50 7
pIC50 9.0 (IC50 1x10-9 M) [7]
mivavotinib Hs Inhibition 8.5 pIC50 16
pIC50 8.5 (IC50 3.2x10-9 M) [16]
Description: Enzyme inhibition in vitro.
compound 23 [PMID: 17600705] Hs Inhibition 8.4 pIC50 2
pIC50 8.4 (IC50 4x10-9 M) [2]
GSK143 Hs Inhibition 8.1 pIC50 18
pIC50 8.1 (IC50 7.5x10-9 M) [18]
Description: Enzyme inhibition assay using recombinant human protein
entospletinib Hs Inhibition 8.1 pIC50 8
pIC50 8.1 (IC50 7.7x10-9 M) [8]
ASN002 Hs Inhibition >8.0 pIC50 26
pIC50 >8.0 (IC50 <1x10-8 M) [26]
lanraplenib Hs Inhibition 7.9 pIC50 4
pIC50 7.9 (IC50 1.35x10-8 M) [4]
Syk inhibitor Hs Inhibition 7.8 pIC50 15
pIC50 7.8 (IC50 1.4x10-8 M) [15]
Description: Assayed using N-Flag tagged catalytic domain of human SYK (Ala340-Asn635)
BAY 61-3606 Hs Inhibition 7.6 pIC50 17
pIC50 7.6 (IC50 2.55x10-8 M) [17]
tamatinib Hs Inhibition 7.4 – 7.8 pIC50 5,19,29
pIC50 7.8 (IC50 1.7x10-8 M) [19]
Description: Measuring inhibition of the capacity of a truncated construct of Syk (aa 360-635) to phosphorylate a biotinylated peptide substrate.
pIC50 7.4 – 7.5 (IC50 4.1x10-8 – 3x10-8 M) [5,29]
cerdulatinib Hs Inhibition 7.5 pIC50 6
pIC50 7.5 (IC50 3.2x10-8 M) [6]
Syk inhibitor II Hs Inhibition 7.4 pIC50 14
pIC50 7.4 (IC50 4.1x10-8 M) [14]
GSK2646264 Hs Inhibition 7.1 pIC50 3
pIC50 7.1 (IC50 7.94x10-8 M) [3]
apitolisib Hs Inhibition 6.9 pIC50 25
pIC50 6.9 (IC50 1.34x10-7 M) [25]
compound 7 [PMID: 22464456] Hs Inhibition 6.4 pIC50 20
pIC50 6.4 (IC50 3.582x10-7 M) [20]
lazertinib Hs Inhibition 6.0 – 6.7 pIC50 24
pIC50 6.0 – 6.7 (IC50 1x10-6 – 2.01x10-7 M) [24]
Description: In a biochemical enzyme activity assay.
Syk inhibitor III Hs Inhibition 5.6 pIC50 27
pIC50 5.6 (IC50 2.8x10-6 M) [27]
ER-27319 Hs Inhibition 5.0 pIC50 23
pIC50 5.0 (IC50 1x10-5 M) [23]
Description: Inhibition of Syk in human mast cells by immunoprecipitation assay
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 9,28

Key to terms and symbols Click column headers to sort
Target used in screen: SYK
Ligand Sp. Type Action Value Parameter
lestaurtinib Hs Inhibitor Inhibition 8.0 pKd
staurosporine Hs Inhibitor Inhibition 7.8 pKd
tamatinib Hs Inhibitor Inhibition 7.7 pKd
midostaurin Hs Inhibitor Inhibition 7.1 pKd
foretinib Hs Inhibitor Inhibition 6.6 pKd
bosutinib Hs Inhibitor Inhibition 6.5 pKd
PD-173955 Hs Inhibitor Inhibition 6.4 pKd
AST-487 Hs Inhibitor Inhibition 6.2 pKd
KW-2449 Hs Inhibitor Inhibition 6.2 pKd
NVP-TAE684 Hs Inhibitor Inhibition 5.9 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 1,10

Key to terms and symbols Click column headers to sort
Target used in screen: Syk/SYK
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 4.7 1.0 0.5
K-252a Hs Inhibitor Inhibition 6.0 1.0 2.0
Gö 6976 Hs Inhibitor Inhibition 14.6 3.0 5.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 15.5 16.0 3.0
Syk inhibitor II Hs Inhibitor Inhibition 15.6 6.0 0.0
SB 218078 Hs Inhibitor Inhibition 15.8 90.0 80.0
Syk inhibitor Hs Inhibitor Inhibition 16.5 38.0 28.0
midostaurin Hs Inhibitor Inhibition 16.8 2.0 3.0
bosutinib Hs Inhibitor Inhibition 21.1
TWS119 Hs Inhibitor Inhibition 36.1 18.0 3.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
SYK plays a key role in coupling activated immunoreceptors to downstream cellular responses such as proliferation, differentiation, and phagocytosis. Mast cell, macrophage and B-cell activation (and release of inflammatory modulators) is disrupted by inhibition of SYK-mediated immunoreceptor signalling. Selective SYK inhibitors are being sought for a number of inflammatory conditions including rheumatoid arthritis, B-cell lymphoma and asthma/rhinitis [11,22].

The first SYK inhibitor to receive FDA approval was fostamatinib (April 2018), which was authorised for the treatment of persistent/chronic adult immune thrombocytopenia (ITP) [21]. In ITP, SYK-mediated signal transduction in macrophages drives the phagocytosis and destruction of autoantibody-coated platelets.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 11 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
GO:0002281 macrophage activation involved in immune response ISS
GO:0002283 neutrophil activation involved in immune response ISS
GO:0002366 leukocyte activation involved in immune response ISS
GO:0002554 serotonin secretion by platelet ISS
GO:0030593 neutrophil chemotaxis IDA
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS
GO:0043306 positive regulation of mast cell degranulation IBA
GO:0043313 regulation of neutrophil degranulation ISS
GO:0045087 innate immune response ISS
GO:0050764 regulation of phagocytosis ISS
Immuno Process:  Antigen presentation
GO Annotations:  Associated to 2 GO processes
GO:0031623 receptor internalization ISS
click arrow to show/hide IEA associations
GO:0002092 positive regulation of receptor internalization IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 5 GO processes
GO:0002250 adaptive immune response ISS
GO:0046641 positive regulation of alpha-beta T cell proliferation IBA
click arrow to show/hide IEA associations
GO:0043366 beta selection IEA
GO:0045588 positive regulation of gamma-delta T cell differentiation IEA
GO:0046638 positive regulation of alpha-beta T cell differentiation IEA
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 2 GO processes
GO:0002250 adaptive immune response ISS
GO:0045579 positive regulation of B cell differentiation IMP
Immuno Process:  Immune regulation
GO Annotations:  Associated to 11 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
GO:0038095 Fc-epsilon receptor signaling pathway TAS
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS
GO:0043306 positive regulation of mast cell degranulation IBA
GO:0043313 regulation of neutrophil degranulation ISS
GO:0045579 positive regulation of B cell differentiation IMP
GO:0046641 positive regulation of alpha-beta T cell proliferation IBA
GO:0050776 regulation of immune response ISO
GO:0050853 B cell receptor signaling pathway ISS
click arrow to show/hide IEA associations
GO:0045588 positive regulation of gamma-delta T cell differentiation IEA
GO:0046638 positive regulation of alpha-beta T cell differentiation IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 4 GO processes
GO:0045579 positive regulation of B cell differentiation IMP
click arrow to show/hide IEA associations
GO:0043366 beta selection IEA
GO:0045588 positive regulation of gamma-delta T cell differentiation IEA
GO:0046638 positive regulation of alpha-beta T cell differentiation IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 14 GO processes
GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway IMP
GO:0032753 positive regulation of interleukin-4 production ISS
GO:0038110 interleukin-2-mediated signaling pathway TAS
GO:0038156 interleukin-3-mediated signaling pathway ISS
GO:0042535 positive regulation of tumor necrosis factor biosynthetic process IMP
GO:0045082 positive regulation of interleukin-10 biosynthetic process IMP
GO:0045084 positive regulation of interleukin-12 biosynthetic process IMP
GO:0045410 positive regulation of interleukin-6 biosynthetic process IMP
GO:0045416 positive regulation of interleukin-8 biosynthetic process IMP
GO:0071639 positive regulation of monocyte chemotactic protein-1 production IMP
click arrow to show/hide IEA associations
GO:0032481 positive regulation of type I interferon production IEA
GO:0045401 positive regulation of interleukin-3 biosynthetic process IEA
GO:0045425 positive regulation of granulocyte macrophage colony-stimulating factor biosynthetic process IEA
GO:0050715 positive regulation of cytokine secretion IEA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 6 GO processes
GO:0007159 leukocyte cell-cell adhesion IDA
GO:0030593 neutrophil chemotaxis IDA
GO:0046641 positive regulation of alpha-beta T cell proliferation IBA
GO:0071639 positive regulation of monocyte chemotactic protein-1 production IMP
click arrow to show/hide IEA associations
GO:0045588 positive regulation of gamma-delta T cell differentiation IEA
GO:0046638 positive regulation of alpha-beta T cell differentiation IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 14 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
GO:0002281 macrophage activation involved in immune response ISS
GO:0002283 neutrophil activation involved in immune response ISS
GO:0002366 leukocyte activation involved in immune response ISS
GO:0038095 Fc-epsilon receptor signaling pathway TAS
GO:0038096 Fc-gamma receptor signaling pathway involved in phagocytosis TAS
GO:0043306 positive regulation of mast cell degranulation IBA
GO:0043313 regulation of neutrophil degranulation ISS
GO:0045579 positive regulation of B cell differentiation IMP
GO:0046641 positive regulation of alpha-beta T cell proliferation IBA
GO:0050853 B cell receptor signaling pathway ISS
click arrow to show/hide IEA associations
GO:0043366 beta selection IEA
GO:0045588 positive regulation of gamma-delta T cell differentiation IEA
GO:0046638 positive regulation of alpha-beta T cell differentiation IEA

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

2. Bamborough P, Angell RM, Bhamra I, Brown D, Bull J, Christopher JA, Cooper AW, Fazal LH, Giordano I, Hind L et al.. (2007) N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics. Bioorg. Med. Chem. Lett., 17 (15): 4363-8. [PMID:17600705]

3. Barker MD, Liddle J, Atkinson FL, Wilson DM, Dickson MC, Ramirez-Molina C, Lewis H, Davis RP, Somers DO, Neu M et al.. (2018) Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease. Bioorg. Med. Chem. Lett., 28 (21): 3458-3462. [PMID:30249354]

4. Blomgren P, Currie KS, Kropf JE, Lee SH, Lo JR, Mitchell SA, Schmitt AC, Xiong J-M, Xu J, Zhao Z et al.. (2016) Substituted imidazo[1,2-a]pyrazines as Syk inhibitors. Patent number: US9290505. Assignee: Gilead Sciences, Inc.. Priority date: 23/12/2013. Publication date: 22/03/2016.

5. Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Baluom M, Qu K, Herlaar E, Lau A, Young C et al.. (2006) R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J. Pharmacol. Exp. Ther., 319 (3): 998-1008. [PMID:16946104]

6. Coffey G, Betz A, DeGuzman F, Pak Y, Inagaki M, Baker DC, Hollenbach SJ, Pandey A, Sinha U. (2014) The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J. Pharmacol. Exp. Ther., 351 (3): 538-48. [PMID:25253883]

7. Coffey G, DeGuzman F, Inagaki M, Pak Y, Delaney SM, Ives D, Betz A, Jia ZJ, Pandey A, Baker D et al.. (2012) Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis. J. Pharmacol. Exp. Ther., 340 (2): 350-9. [PMID:22040680]

8. Currie KS, Kropf JE, Lee T, Blomgren P, Xu J, Zhao Z, Gallion S, Whitney JA, Maclin D, Lansdon EB et al.. (2014) Discovery of GS-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase. J. Med. Chem., 57 (9): 3856-73. [PMID:24779514]

9. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

10. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

11. Ghosh D, Tsokos GC. (2010) Spleen tyrosine kinase: an Src family of non-receptor kinase has multiple functions and represents a valuable therapeutic target in the treatment of autoimmune and inflammatory diseases. Autoimmunity, 43 (1): 48-55. [PMID:20001666]

12. Grädler U, Schwarz D, Dresing V, Musil D, Bomke J, Frech M, Greiner H, Jäkel S, Rysiok T, Müller-Pompalla D et al.. (2013) Structural and biophysical characterization of the Syk activation switch. J. Mol. Biol., 425 (2): 309-33. [PMID:23154170]

13. Hayashi H, Kaneko R, Demizu S, Akasaka D, Tayama M, Harada T, Irie H, Ogino Y, Fujino N, Sasaki E. (2018) TAS05567, a Novel Potent and Selective Spleen Tyrosine Kinase Inhibitor, Abrogates Immunoglobulin-Mediated Autoimmune and Allergic Reactions in Rodent Models. J. Pharmacol. Exp. Ther., 366 (1): 84-95. DOI: 10.1124/jpet.118.248153 [PMID:29728446]

14. Hisamichi H, Naito R, Toyoshima A, Kawano N, Ichikawa A, Orita A, Orita M, Hamada N, Takeuchi M, Ohta M et al.. (2005) Synthetic studies on novel Syk inhibitors. Part 1: Synthesis and structure-activity relationships of pyrimidine-5-carboxamide derivatives. Bioorg. Med. Chem., 13 (16): 4936-51. [PMID:15990316]

15. Lai JY, Cox PJ, Patel R, Sadiq S, Aldous DJ, Thurairatnam S, Smith K, Wheeler D, Jagpal S, Parveen S et al.. (2003) Potent small molecule inhibitors of spleen tyrosine kinase (Syk). Bioorg. Med. Chem. Lett., 13 (18): 3111-4. [PMID:12941345]

16. Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A et al.. (2016) Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK). Bioorg. Med. Chem. Lett., 26 (24): 5947-5950. [PMID:27839918]

17. Lau KS, Zhang T, Kendall KR, Lauffenburger D, Gray NS, Haigis KM. (2012) BAY61-3606 affects the viability of colon cancer cells in a genotype-directed manner. PLoS ONE, 7 (7): e41343. [PMID:22815993]

18. Liddle J, Atkinson FL, Barker MD, Carter PS, Curtis NR, Davis RP, Douault C, Dickson MC, Elwes D, Garton NS et al.. (2011) Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor. Bioorg. Med. Chem. Lett., 21 (20): 6188-94. [PMID:21903390]

19. Lucas MC, Goldstein DM, Hermann JC, Kuglstatter A, Liu W, Luk KC, Padilla F, Slade M, Villaseñor AG, Wanner J et al.. (2012) Rational design of highly selective spleen tyrosine kinase inhibitors. J. Med. Chem., 55 (23): 10414-23. [PMID:23151054]

20. McLean LR, Zhang Y, Zaidi N, Bi X, Wang R, Dharanipragada R, Jurcak JG, Gillespy TA, Zhao Z, Musick KY et al.. (2012) X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase. Bioorg. Med. Chem. Lett., 22 (9): 3296-300. [PMID:22464456]

21. Newland A, Lee EJ, McDonald V, Bussel JB. (2018) Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy, 10 (1): 9-25. [PMID:28967793]

22. Riccaboni M, Bianchi I, Petrillo P. (2010) Spleen tyrosine kinases: biology, therapeutic targets and drugs. Drug Discov. Today, 15 (13-14): 517-30. [PMID:20553955]

23. Singh R, Masuda ES, Payan DG. (2012) Discovery and development of spleen tyrosine kinase (SYK) inhibitors. J. Med. Chem., 55 (8): 3614-43. [PMID:22257213]

24. Suh B-C, Salgaonkar PD, Lee J, Koh JS, Song H-J, Lee IY, Lee J, Jung DS, Kim J-H, Kim S-W. (2016) Compounds and compositions for modulating EGFR mutant kinase activities. Patent number: WO2016060443A2. Assignee: Yuhan Corporation. Priority date: 13/10/2014. Publication date: 21/04/2016.

25. Sutherlin DP, Bao L, Berry M, Castanedo G, Chuckowree I, Dotson J, Folks A, Friedman L, Goldsmith R, Gunzner J et al.. (2011) Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J. Med. Chem., 54 (21): 7579-87. [PMID:21981714]

26. Venkatesan A, Smith RS, Hosahalli S, Potluri V, Panigrahi SK, Basetti V, Kuntu K. (2013) Pyrimido- pyridazinone compounds and use thereof. Patent number: WO2013028818A1. Assignee: Asana Biosciences LLC. Priority date: 23/08/2011. Publication date: 28/02/2013.

27. Wang WY, Hsieh PW, Wu YC, Wu CC. (2007) Synthesis and pharmacological evaluation of novel beta-nitrostyrene derivatives as tyrosine kinase inhibitors with potent antiplatelet activity. Biochem. Pharmacol., 74 (4): 601-11. [PMID:17601492]

28. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

29. Xie HZ, Li LL, Ren JX, Zou J, Yang L, Wei YQ, Yang SY. (2009) Pharmacophore modeling study based on known spleen tyrosine kinase inhibitors together with virtual screening for identifying novel inhibitors. Bioorg. Med. Chem. Lett., 19 (7): 1944-9. [PMID:19254842]

How to cite this page

Syk family: spleen associated tyrosine kinase. Last modified on 12/03/2019. Accessed on 20/11/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2230.