Bruton tyrosine kinase | Tec family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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Bruton tyrosine kinase

Target id: 1948

Nomenclature: Bruton tyrosine kinase

Abbreviated Name: Btk

Family: Tec family

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

   GtoImmuPdb view: ON :     Bruton tyrosine kinase has curated data in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 659 Xq21.33-q22 BTK Bruton tyrosine kinase
Mouse - 659 X E3 Btk Bruton agammaglobulinemia tyrosine kinase
Rat - 660 X q34 Btk Bruton tyrosine kinase
Previous and Unofficial Names
AGMX1 | ATK | B-cell progenitor kinase | IMD1 | PSCTK1 | xid | X-linked immune deficiency | Bruton agammaglobulinemia tyrosine kinase
Database Links
BRENDA
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  The 1.6 A crystal structure of human bruton's tyrosine kinase bound to a pyrrolopyrimidine-containing compound
PDB Id:  3GEN
Resolution:  1.6Å
Species:  Human
References:  22
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the kinase domain of Bruton's Tyrosine kinase with GDC0834
PDB Id:  4OTF
Ligand:  GDC-0834
Resolution:  1.95Å
Species:  Human
References:  35
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 Affinity Units Reference
RN486 Hs Inhibition 9.5 pKd 32
pKd 9.5 (Kd 3.1x10-10 M) [32]
WZ4002 Hs Inhibition 7.4 pKd 37
pKd 7.4 (Kd 4.3x10-8 M) [37]
acalabrutinib Hs Inhibition >8.0 pEC50 3
pEC50 >8.0 (EC50 <1x10-8 M) [3]
BMS-986195 Hs Inhibition 10.0 pIC50 19
pIC50 10.0 (IC50 1.1x10-10 M) [19]
Description: Evaluated in a FLIPR calcium mobilisation assay in Ramos B lymphocytes.
BGB-3111 Hs Inhibition 9.8 pIC50 27
pIC50 9.8 (IC50 1.7x10-10 M) [27]
AC0010 Hs Inhibition 9.4 pIC50 33
pIC50 9.4 (IC50 4x10-10 M) [33]
Description: In a biochemical assay.
spebrutinib Hs Inhibition >9.3 pIC50 12
pIC50 >9.3 (IC50 <5x10-10 M) [12]
BMS-986142 Hs Inhibition 9.3 pIC50 29
pIC50 9.3 (IC50 5x10-10 M) [29]
BTK inhibitor 16 [PMID: 30122225] Hs Inhibition 9.1 pIC50 25
pIC50 9.1 (IC50 7x10-10 M) [25]
Description: Using a microfluidic, off-chip mobility shift kinase assay with FITC-AHA-EEPLYWSFPAKKK-NH2 as peptide substrate.
ibrutinib Hs Inhibition 8.8 – 9.3 pIC50 6,24
pIC50 9.3 (IC50 5x10-10 M) [24]
pIC50 8.8 (IC50 1.5x10-9 M) [6]
CNX-774 Hs Inhibition >9.0 pIC50 2
pIC50 >9.0 (IC50 <1x10-9 M) [2]
PRN1008 Hs Inhibition 8.8 pIC50 23
pIC50 8.8 (IC50 1.5x10-9 M) [23]
Description: Measured in a caliper-based kinase assay, to assess inhibition of recombinant human BTK kinase activity (@ 16 μM ATP) using the phosphoacceptor peptide substrate FAM-GEEPLYWSFPAKKK-NH2.
CGI1746 Hs Inhibition 8.7 pIC50 10
pIC50 8.7 (IC50 1.9x10-9 M) [10]
compound 9 [PMID: 26006010] Hs Inhibition 8.7 pIC50 5
pIC50 8.7 (IC50 1.9x10-9 M) [5]
compound 36 [PMID: 21958547] Hs Inhibition 8.7 pIC50 16
pIC50 8.7 (IC50 1.93x10-9 M) [16]
zanubrutinib Hs Inhibition 8.7 pIC50 28
pIC50 8.7 (IC50 2x10-9 M) [28]
Description: Inhibition of the enzymatic activity of recombinant human BTK in a TR-FRET assay.
compound 2c [PMID: 24900538] Hs Inhibition 8.5 pIC50 26
pIC50 8.5 (IC50 3.5x10-9 M) [26]
tirabrutinib Hs Inhibition 8.4 pIC50 34
pIC50 8.4 (IC50 4x10-9 M) [34]
compound 38 [PMID: 24915291] Hs Inhibition >8.4 pIC50 17
pIC50 >8.4 (IC50 <4.4x10-9 M) [17]
compound 31 [PMID: 24915291] Hs Inhibition 8.4 pIC50 17
pIC50 8.4 (IC50 5x10-9 M) [17]
acalabrutinib Hs Inhibition 8.3 pIC50 6
pIC50 8.3 (IC50 5.1x10-9 M) [6]
GDC-0834 Hs Inhibition 8.2 pIC50 35
pIC50 8.2 (IC50 6x10-9 M) [35]
PRN694 Hs Inhibition 7.8 pIC50 36
pIC50 7.8 (IC50 1.7x10-8 M) [36]
CHMFL-BTK-11 Hs Irreversible inhibition 7.6 pIC50 31
pIC50 7.6 (IC50 2.682x10-8 M) [31]
poseltinib Hs Inhibition >7.3 pIC50 7
pIC50 >7.3 (IC50 <5x10-8 M) [7]
Description: Biochemical assay result. Binned IC50 value provided in patent.
evobrutinib Hs Inhibition >7.0 pIC50 14
pIC50 >7.0 (IC50 <1x10-7 M) [14]
Description: Binned value derived from a time-dependent BTK enzyme assay.
CGI560 Hs Inhibition 6.4 pIC50 20
pIC50 6.4 (IC50 4x10-7 M) [20]
LFM-A13 Hs Inhibition 4.8 pIC50 21
pIC50 4.8 (IC50 1.72x10-5 M) [21]
Description: IN a cell-free BTK assay using BTK immunoprecipitated from B18.2 cells.
fenebrutinib Hs Inhibition - - 8
[8]
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: 9,30

Key to terms and symbols Click column headers to sort
Target used in screen: BTK
Ligand Sp. Type Action Affinity Units
dasatinib Hs Inhibitor Inhibition 8.9 pKd
bosutinib Hs Inhibitor Inhibition 8.3 pKd
NVP-TAE684 Hs Inhibitor Inhibition 7.6 pKd
lestaurtinib Hs Inhibitor Inhibition 7.2 pKd
foretinib Hs Inhibitor Inhibition 7.1 pKd
JNJ-28312141 Hs Inhibitor Inhibition 7.1 pKd
neratinib Hs Inhibitor Inhibition 6.8 pKd
tamatinib Hs Inhibitor Inhibition 6.7 pKd
staurosporine Hs Inhibitor Inhibition 6.7 pKd
PD-173955 Hs Inhibitor Inhibition 6.7 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: 1,13

Key to terms and symbols Click column headers to sort
Target used in screen: BTK/BTK
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
dasatinib Hs Inhibitor Inhibition 2.1
EGFR/ErbB-2/ErbB-4 inhibitor Hs Inhibitor Inhibition 2.9 47.0 16.0
Lck inhibitor Hs Inhibitor Inhibition 4.6 1.0 1.0
bosutinib Hs Inhibitor Inhibition 5.7
staurosporine Hs Inhibitor Inhibition 7.8 2.5 -1.0
K-252a Hs Inhibitor Inhibition 8.9 -1.0 -1.0
GSK-3 inhibitor IX Hs Inhibitor Inhibition 13.1 1.0 0.0
vandetanib Hs Inhibitor Inhibition 17.6
Gö 6976 Hs Inhibitor Inhibition 22.0 10.0 9.0
indirubin derivative E804 Hs Inhibitor Inhibition 24.1 12.0 -2.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
Disease:  Agammaglobulinemia, X-linked
Synonyms: Bruton-type agammaglobulinemia [Disease Ontology: DOID:14179]
Disease Ontology: DOID:14179
OMIM: 300755
Orphanet: ORPHA47
Disease:  Isolated growth hormone deficiency, Type III
Synonyms: Short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia
OMIM: 307200
Orphanet: ORPHA632
General Comments
The history, and pros and cons of the various small molecule BTK inhibitor classes that have been developed for clinical applications, and prospects for future drug design are reviewed by Liang et al. (2018) [18].

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. Barf T, Kaptein A. (2012) Irreversible protein kinase inhibitors: balancing the benefits and risks. J. Med. Chem., 55 (14): 6243-62. [PMID:22621397]

3. Barf TA, Jans CGJM, Man PADeA, Oubrie AA, Raaijmakers HCA, Rewinkel JBM, Sterrenburg J-G, Wijkmans JCHM. (2014) 4-imidazopyridazin-1-yl-benzamides and 4-imidazotriazin-1-yl-benzamides as btk inhibitors. Patent number: US20140155385 A1. Assignee: Barf TA, Jans CGJM, Man PADeA, Oubrie AA, Raaijmakers HCA, Rewinkel JBM, Sterrenburg J-G, Wijkmans JCHM. Priority date: 19/07/2011. Publication date: 05/06/2014.

4. Berg LJ, Finkelstein LD, Lucas JA, Schwartzberg PL. (2005) Tec family kinases in T lymphocyte development and function. Annu. Rev. Immunol., 23: 549-600. [PMID:15771581]

5. Bradshaw JM, McFarland JM, Paavilainen VO, Bisconte A, Tam D, Phan VT, Romanov S, Finkle D, Shu J, Patel V et al.. (2015) Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat. Chem. Biol., 11 (7): 525-31. [PMID:26006010]

6. Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR et al.. (2016) Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N. Engl. J. Med., 374 (4): 323-32. [PMID:26641137]

7. Cha MY, Kang SJ, Kim MR, Lee JY, Jeon JY, Jo MG, Kwak EJ, Lee KO, Ha TH, Suh KH, Kim MS. (2011) Novel fused pyrimidine derivatives for inhd3ition of tyrosine kinase activity. Patent number: WO2011162515A2. Assignee: Hanmi Holdings Co. , Ltd.. Priority date: 23/06/2010. Publication date: 29/12/2011.

8. Crawford JJ, Ortwine DF, Wei B, Young WB. (2013) Heteroaryl pyridone and aza-pyridone compounds as inhibitors of btk activity. Patent number: WO2013067274. Assignee: Genentech, Inc.. Priority date: 03/11/2011. Publication date: 10/05/2013.

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. Di Paolo JA, Huang T, Balazs M, Barbosa J, Barck KH, Bravo BJ, Carano RA, Darrow J, Davies DR, DeForge LE et al.. (2011) Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. Nat. Chem. Biol., 7 (1): 41-50. [PMID:21113169]

11. Doyle SL, Jefferies CA, Feighery C, O'Neill LA. (2007) Signaling by Toll-like receptors 8 and 9 requires Bruton's tyrosine kinase. J. Biol. Chem., 282 (51): 36953-60. [PMID:17932028]

12. Evans E, Tester R, Aslanian S, Mazdiyasn H, Ponader S, Tesar B, Chaturvedi P, Nacht M, Stiede K, Witowski S et al.. Clinical Development of AVL - 292: A Potent, Selective Covalent Btk Inhibitor for the Treatment of B Cell Malignancies. Accessed on 29/10/2014. Modified on 29/10/2014. http://www.celgene.com, http://www.celgene.com/content/uploads/pdf/2011_ASH_AVL-292.pdf

13. 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]

14. Hodous B, Liu-Bujalski L, Jones R, Bankston D, Johnson TL, Mochalkin I, Nguyen N, Qiu H, Goutopoulos A, Brugger N. (2012) Compositions and methods for the production of pyrimidine and pyridine compounds with btk inhibitory activity. Patent number: WO2012170976. Assignee: Merck Patent Gmbh. Priority date: 10/06/2011. Publication date: 13/12/2012.

15. Horwood NJ, Page TH, McDaid JP, Palmer CD, Campbell J, Mahon T, Brennan FM, Webster D, Foxwell BM. (2006) Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production. J. Immunol., 176 (6): 3635-41. [PMID:16517732]

16. Kim KH, Maderna A, Schnute ME, Hegen M, Mohan S, Miyashiro J, Lin L, Li E, Keegan S, Lussier J et al.. (2011) Imidazo[1,5-a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis. Bioorg. Med. Chem. Lett., 21 (21): 6258-63. [PMID:21958547]

17. Li X, Zuo Y, Tang G, Wang Y, Zhou Y, Wang X, Guo T, Xia M, Ding N, Pan Z. (2014) Discovery of a series of 2,5-diaminopyrimidine covalent irreversible inhibitors of Bruton's tyrosine kinase with in vivo antitumor activity. J. Med. Chem., 57 (12): 5112-28. [PMID:24915291]

18. Liang C, Tian D, Ren X, Ding S, Jia M, Xin M, Thareja S. (2018) The development of Bruton's tyrosine kinase (BTK) inhibitors from 2012 to 2017: A mini-review. Eur J Med Chem, 151: 315-326. [PMID:29631132]

19. Liu Q, Watterson SH, Batt DG, Ahmad S, Bertrand MB, Gong H, Guo W, Macor JE, Ngu K, Tebben J, Tino A. (2016) Indole carboxamide compounds. Patent number: US20160115126A1. Assignee: Bristol-Myers Squibb Co. Priority date: 24/10/2014. Publication date: 28/04/2016.

20. Lou Y, Owens TD, Kuglstatter A, Kondru RK, Goldstein DM. (2012) Bruton's tyrosine kinase inhibitors: approaches to potent and selective inhibition, preclinical and clinical evaluation for inflammatory diseases and B cell malignancies. J. Med. Chem., 55 (10): 4539-50. [PMID:22394077]

21. Mahajan S, Ghosh S, Sudbeck EA, Zheng Y, Downs S, Hupke M, Uckun FM. (1999) Rational design and synthesis of a novel anti-leukemic agent targeting Bruton's tyrosine kinase (BTK), LFM-A13 [alpha-cyano-beta-hydroxy-beta-methyl-N-(2, 5-dibromophenyl)propenamide]. J. Biol. Chem., 274 (14): 9587-99. [PMID:10092645]

22. Marcotte DJ, Liu YT, Arduini RM, Hession CA, Miatkowski K, Wildes CP, Cullen PF, Hong V, Hopkins BT, Mertsching E et al.. (2010) Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases. Protein Sci., 19 (3): 429-39. [PMID:20052711]

23. Owens T, Verner E. (2014) PYRAZOLOPYRIMIDINE COMPOUNDS AS KINASE INHIBITORS. Patent number: WO2014039899. Assignee: Principia Biopharma. Priority date: 06/09/2013. Publication date: 13/03/2014.

24. Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC, Mendonca RV, Sweeney MD, Scott KC, Grothaus PG et al.. (2007) Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. ChemMedChem, 2 (1): 58-61. [PMID:17154430]

25. Qiu H, Liu-Bujalski L, Caldwell RD, Follis AV, Gardberg A, Goutopoulos A, Grenningloh R, Head J, Johnson T, Jones R et al.. (2018) Discovery of potent, highly selective covalent irreversible BTK inhibitors from a fragment hit. Bioorg. Med. Chem. Lett., 28 (17): 2939-2944. [PMID:30122225]

26. Wang T, Lamb ML, Block MH, Davies AM, Han Y, Hoffmann E, Ioannidis S, Josey JA, Liu ZY, Lyne PD et al.. (2012) Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors. ACS Med Chem Lett, 3 (9): 705-9. [PMID:24900538]

27. Wang Z, Guo Y. (2015) Protein Kinase Inhibitors and Uses Thereof. Patent number: US20150005277. Assignee: Beigene, Ltd.. Priority date: 28/06/2013. Publication date: 01/01/2015.

28. Wang Z, Guo Y. (2016) Substituted pyrazolo[1,5-a]pyrimidines as bruton's tyrosine kinase modulators. Patent number: US9447106B2. Assignee: Beigene Ltd.. Priority date: 25/04/2013. Publication date: 20/09/2016.

29. Watterson SH, De Lucca GV, Shi Q, Langevine CM, Liu Q, Batt DG, Beaudoin Bertrand M, Gong H, Dai J, Yip S et al.. (2016) Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers. J. Med. Chem., 59 (19): 9173-9200. [PMID:27583770]

30. 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]

31. Wu H, Huang Q, Qi Z, Chen Y, Wang A, Chen C, Liang Q, Wang J, Chen W, Dong J et al.. (2017) Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model. Sci Rep, 7 (1): 466. [PMID:28352114]

32. Xu D, Kim Y, Postelnek J, Vu MD, Hu DQ, Liao C, Bradshaw M, Hsu J, Zhang J, Pashine A et al.. (2012) RN486, a selective Bruton's tyrosine kinase inhibitor, abrogates immune hypersensitivity responses and arthritis in rodents. J. Pharmacol. Exp. Ther., 341 (1): 90-103. [PMID:22228807]

33. Xu X, Mao L, Xu W, Tang W, Zhang X, Xi B, Xu R, Fang X, Liu J, Fang C et al.. (2016) AC0010, an Irreversible EGFR Inhibitor Selectively Targeting Mutated EGFR and Overcoming T790M-Induced Resistance in Animal Models and Lung Cancer Patients. Mol. Cancer Ther., 15 (11): 2586-2597. [PMID:27573423]

34. Yamamoto S, Yoshizawa T. (2011) Purinone derivative. Patent number: WO2011152351. Assignee: Ono Pharmaceutical Co., Ltd.. Priority date: 31/05/2010. Publication date: 08/12/2011.

35. Young WB, Barbosa J, Blomgren P, Bremer MC, Crawford JJ, Dambach D, Gallion S, Hymowitz SG, Kropf JE, Lee SH et al.. (2015) Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834. Bioorg. Med. Chem. Lett., 25 (6): 1333-7. [PMID:25701252]

36. Zhong Y, Dong S, Strattan E, Ren L, Butchar JP, Thornton K, Mishra A, Porcu P, Bradshaw JM, Bisconte A et al.. (2015) Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694. J. Biol. Chem., 290 (10): 5960-78. [PMID:25593320]

37. Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, Padera R et al.. (2009) Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature, 462 (7276): 1070-4. [PMID:20033049]

How to cite this page

Tec family: Bruton tyrosine kinase. Last modified on 07/09/2018. Accessed on 16/01/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1948.