Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTGM6VW)

• DTT Name: Tyrosine-protein kinase BTK (ATK)
• Synonyms: Bruton's tyrosine kinase; Bruton tyrosine kinase; BPK; B-cell progenitor kinase; B cell progenitor kinase; Agammaglobulinemia tyrosine kinase; Agammaglobulinaemia tyrosine kinase; AGMX1
• Gene Name: BTK
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: BTK_HUMAN
• TTD ID: T25005
• EC Number: EC 2.7.10.2
• Sequence:
  MAAVILESIFLKRSQQKKKTSPLNFKKRLFLLTVHKLSYYEYDFERGRRGSKKGSIDVEK
  ITCVETVVPEKNPPPERQIPRRGEESSEMEQISIIERFPYPFQVVYDEGPLYVFSPTEEL
  RKRWIHQLKNVIRYNSDLVQKYHPCFWIDGQYLCCSQTAKNAMGCQILENRNGSLKPGSS
  HRKTKKPLPPTPEEDQILKKPLPPEPAAAPVSTSELKKVVALYDYMPMNANDLQLRKGDE
  YFILEESNLPWWRARDKNGQEGYIPSNYVTEAEDSIEMYEWYSKHMTRSQAEQLLKQEGK
  EGGFIVRDSSKAGKYTVSVFAKSTGDPQGVIRHYVVCSTPQSQYYLAEKHLFSTIPELIN
  YHQHNSAGLISRLKYPVSQQNKNAPSTAGLGYGSWEIDPKDLTFLKELGTGQFGVVKYGK
  WRGQYDVAIKMIKEGSMSEDEFIEEAKVMMNLSHEKLVQLYGVCTKQRPIFIITEYMANG
  CLLNYLREMRHRFQTQQLLEMCKDVCEAMEYLESKQFLHRDLAARNCLVNDQGVVKVSDF
  GLSRYVLDDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYER
  FTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNILDVMDEES
• Function: Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis. Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling.
• KEGG Pathway:
  NF-kappa B signaling pathway (hsa04064)
  Osteoclast differentiation (hsa04380)
  Platelet activation (hsa04611)
  B cell receptor signaling pathway (hsa04662)
  Fc epsilon RI signaling pathway (hsa04664)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)
  DAP12 signaling (R-HSA-2424491)
  FCERI mediated Ca+2 mobilization (R-HSA-2871809)
  MyD88 deficiency (TLR2/4) (R-HSA-5602498)
  IRAK4 deficiency (TLR2/4) (R-HSA-5603041)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695)
  MyD88 (R-HSA-166058)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Acalabrutinib	DM7GCVW	leukaemia	2A60-2B33	Approved	[2]
Ibrutinib	DMHZCPO	Mantle cell lymphoma	2A85.5	Approved	[3]
Pirtobrutinib	DMRG1X3	Non-hodgkin lymphoma	2B33.5	Approved	[4]
Zanubrutinib	DMJWRQP	Mantle cell lymphoma	2A85.5	Approved	[5]

34 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GDC-0853	DMBEL3Q	Multiple sclerosis	8A40	Phase 3	[6]
ICP-022	DMU72KL	Chronic lymphocytic leukaemia	2A82.0	Phase 3	[7]
Tolebrutinib	DML19V6	Multiple sclerosis	8A40	Phase 3	[8]
ARQ 531	DMRG0A3	Hematologic tumour	2B33.Y	Phase 2	[9]
BGB-3112	DMQCFSM	Follicular lymphoma	2A80	Phase 2	[9]
BMS-986142	DMZB8AJ	Rheumatoid arthritis	FA20	Phase 2	[6]
Branebrutinib	DM97I5L	Rheumatoid arthritis	FA20	Phase 2	[10]
CC-292	DMJR9H0	Chronic lymphocytic leukaemia	2A82.0	Phase 2	[11]
DTRM-555	DMX27IT	Chronic lymphocytic leukaemia	2A82.0	Phase 2	[12]
GS-4059	DMHQV6R	B-cell lymphoma	2A86	Phase 2	[9]
LOU064	DME8O5K	Chronic idiopathic urticaria	EB00.1	Phase 2	[13]
M2951	DMC5MQD	Multiple sclerosis	8A40	Phase 2	[6]
PRN1008	DMBZ6CP	Pemphigus vulgaris	EB40	Phase 2	[6]
SAR 444727	DMWPMN2	Atopic dermatitis	EA80	Phase 2	[14]
ACP-319	DM7IWTF	Chronic lymphocytic leukaemia	2A82.0	Phase 1/2	[3]
CG-806	DMPYW28	Acute myeloid leukaemia	2A60	Phase 1/2	[15]
Vecabrutinib	DM8A5E0	B-cell lymphoma	2A86	Phase 1/2	[9]
AC0058TA	DMB5A63	Autoimmune disease	4A40-4A45	Phase 1	[6]
BGB-16673	DM7X6IB	B-cell lymphoma	2A86	Phase 1	[16]
BGB-3113	DMIF9DZ	B-cell lymphoma	2A86	Phase 1	[9]
BIIB068	DMVS87W	Systemic lupus erythematosus	4A40.0	Phase 1	[6]
BIIB091	DMW49ZF	Multiple sclerosis	8A40	Phase 1	[17]
DTRMWXHS-12	DM5AGKV	B-cell lymphoma	2A86	Phase 1	[18]
HM71224	DME4D7H	Rheumatoid arthritis	FA20	Phase 1	[19]
HMPL-760	DMHC5YG	Chronic lymphocytic leukaemia	2A82.0	Phase 1	[20]
JNJ-64264681	DMLYAGD	Chronic lymphocytic leukaemia	2A82.0	Phase 1	[21]
M7583	DMDK4MG	Haematological malignancy	2B33.Y	Phase 1	[9]
NX-2127	DMIE2OG	Chronic lymphocytic leukaemia	2A82.0	Phase 1	[22]
NX-5948	DM6GHMC	Chronic lymphocytic leukaemia	2A82.0	Phase 1	[22]
ONO-4059	DMC29LV	B-cell lymphoma	2A86	Phase 1	[23]
PRN2246	DMQNS51	Multiple sclerosis	8A40	Phase 1	[24]
TAK-020	DM6OKH4	Rheumatoid arthritis	FA20	Phase 1	[6]
TG-1701	DMNDHKL	Chronic lymphocytic leukaemia	2A82.0	Phase 1	[25]
TT-01488	DMHTGB5	B-cell non-hodgkin lymphoma	2B33.5	Phase 1	[26]

26 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Imidazopyridine derivative 4	DMP2AXV	N. A.	N. A.	Patented	[27]
PMID27774824-Compound-Figure12Example1	DMAGKNJ	N. A.	N. A.	Patented	[27]
PMID27774824-Compound-Figure12Example10	DMYOSIA	N. A.	N. A.	Patented	[27]
PMID27774824-Compound-Figure12Example61	DMNIZD7	N. A.	N. A.	Patented	[27]
Pyrazolo[4,3-c]pyridine derivative 2	DMCDFLQ	N. A.	N. A.	Patented	[27]
Pyrrolo[2,3-d]pyrimidine derivative 12	DMYTV49	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 13	DMTGELI	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 14	DMK4LOH	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 15	DMZ4PLC	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 16	DM1GYZQ	Autoimmune disease	4A40-4A45	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 17	DMXWVN2	Autoimmune disease	4A40-4A45	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 18	DMSXH8K	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 19	DMC9TGM	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 20	DM2E7DJ	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 21	DM9S07A	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 22	DMHWNSD	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 23	DMTMWKX	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 25	DMWU3O4	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 26	DMX1ANB	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 27	DMCZJ1W	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 28	DMXRJI2	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 29	DM6IJRG	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 30	DM57W29	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 31	DMA9PM4	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 32	DMQGI0R	N. A.	N. A.	Patented	[28]
Pyrrolo[2,3-d]pyrimidine derivative 33	DM6BTMX	N. A.	N. A.	Patented	[28]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PCI-45292	DMW3TGI	Autoimmune diabetes	5A10	Preclinical	[29]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GDC-0834	DMOAURL	Rheumatoid arthritis	FA20	Terminated	[30]

7 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CGI-1316	DMTPRBX	Autoimmune diabetes	5A10	Investigative	[3]
Inositol 1,3,4,5-Tetrakisphosphate	DMIFD35	Discovery agent	N.A.	Investigative	[31]
LFM-A13	DMTXWCZ	Discovery agent	N.A.	Investigative	[32]
PMID24900538C2c	DM5PATM	Discovery agent	N.A.	Investigative	[33]
PMID24915291C31	DMN7QB8	Discovery agent	N.A.	Investigative	[34]
PMID24915291C38	DMBXT9J	Discovery agent	N.A.	Investigative	[34]
RN486	DML7SQH	Discovery agent	N.A.	Investigative	[35]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	3.54E-01	0.24	0.56

References

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• [2] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [3] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1948).
• [4] Targeting BTK in CLL: Beyond Ibrutinib. Curr Hematol Malig Rep. 2019 Jun;14(3):197-205.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Clinical pipeline report, company report or official report of InnoCare Pharma.
• [8] Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2021 Sep;20(9):729-738.
• [9] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [10] Safety, pharmacokinetics and pharmacodynamics of branebrutinib (BMS-986195), a covalent, irreversible inhibitor of Bruton's tyrosine kinase: Randomised phase I, placebo-controlled trial in healthy participants. Br J Clin Pharmacol. 2020 Sep;86(9):1849-1859.
• [11] Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans. J Pharmacol Exp Ther. 2013 Aug;346(2):219-28.
• [12] ClinicalTrials.gov (NCT04305444) Study of a Triple Combination Therapy, DTRM-555, in Patients With R/R CLL or R/R Non-Hodgkin's Lymphomas. U.S. National Institutes of Health.
• [13] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [14] Preclinical Mechanisms of Topical PRN473, a Bruton Tyrosine Kinase Inhibitor, in Immune-Mediated Skin Disease Models. Immunohorizons. 2021 Jul 29;5(7):581-589.
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• [16] ClinicalTrials.gov (NCT05294731) A Phase 1, Open-Label, Dose-Escalation and Expansion Study of the Bruton Tyrosine Kinase Targeted Protein-Degrader BGB-16673 in Chinese Patients With B-Cell Malignancies. U.S.National Institutes of Health.
• [17] Discovery and Preclinical Characterization of BIIB091, a Reversible, Selective BTK Inhibitor for the Treatment of Multiple Sclerosis. J Med Chem. 2022 Jan 27;65(2):1206-1224.
• [18] ClinicalTrials.gov (NCT02900716) Safety Study of BTK Inhibitor, DTRMWXHS-12, Used Singly or in Combination, in CLL and B-cell Lymphomas. U.S. National Institutes of Health.
• [19] HM71224, a selective Bruton's tyrosine kinase inhibitor, attenuates the development of murine lupus. Arthritis Res Ther. 2017 Sep 26;19(1):211.
• [20] ClinicalTrials.gov (NCT05176691) A Multicenter, Open-label, Phase 1 Study Evaluating the Safety and Tolerability of HMPL-760 in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Other Non-Hodgkin Lymphoma (NHL). U.S.National Institutes of Health.
• [21] A Study of JNJ-64264681 and JNJ-67856633 in Participants With Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia
• [22] The Evolution of Therapies Targeting Bruton Tyrosine Kinase for the Treatment of Chronic Lymphocytic Leukaemia: Future Perspectives. Cancers (Basel). 2023 May 3;15(9):2596.
• [23] ONO-4059, a novel oral Bruton's tyrosine kinase (Btk) inhibitor that demonstrates potent pharmacodynamic activity through Phosphorylated Btk (P-Btk) inhibition, in addition to effective anti-tumour activity in a TMD-8 (DLBCL) xenograft model. Cancer Research. 08/2013; 73(8 Supplement):2452-2452.
• [24] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [25] Clinical pipeline report, company report or official report of TG Therapeutics.
• [26] ClinicalTrials.gov (NCT05683717) A Phase I, Multicenter, Open Label, and Dose-Escalation Study of TT-01488, Administered Orally in Adult Patients With B-Cell Malignancies. U.S.National Institutes of Health.
• [27] Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 1.Expert Opin Ther Pat. 2017 Feb;27(2):127-143.
• [28] Pyrrolo[2,3-d]pyrimidines active as Btk inhibitors.Expert Opin Ther Pat. 2017 Dec;27(12):1305-1318.
• [29] Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013 October 10; 122(15): 2539-2549.
• [30] Antiarthritis effect of a novel Bruton's tyrosine kinase (BTK) inhibitor in rat collagen-induced arthritis and mechanism-based pharmacokinetic/pharmacodynamic modeling: relationships between inhibition of BTK phosphorylation and efficacy. J Pharmacol Exp Ther. 2011 Jul;338(1):154-63.
• [31] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [32] A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8.
• [33] Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors. ACS Med Chem Lett. 2012 Jul 26;3(9):705-9.
• [34] Discovery of a series of 2,5-diaminopyrimidine covalent irreversible inhibitors of Bruton's tyrosine kinase with in vivo antitumor activity. J Med Chem. 2014 Jun 26;57(12):5112-28.
• [35] RN486, a selective Bruton's tyrosine kinase inhibitor, abrogates immune hypersensitivity responses and arthritis in rodents. J Pharmacol Exp Ther. 2012 Apr;341(1):90-103.