| Structural highlights
Disease
BTK_HUMAN Defects in BTK are the cause of X-linked agammaglobulinemia (XLA) [MIM:300755; also known as X-linked agammaglobulinemia type 1 (AGMX1) or immunodeficiency type 1 (IMD1). XLA is a humoral immunodeficiency disease which results in developmental defects in the maturation pathway of B-cells. Affected boys have normal levels of pre-B-cells in their bone marrow but virtually no circulating mature B-lymphocytes. This results in a lack of immunoglobulins of all classes and leads to recurrent bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis in the first few years of life, or even some patients present overwhelming sepsis or meningitis, resulting in death in a few hours. Treatment in most cases is by infusion of intravenous immunoglobulin.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] Defects in BTK may be the cause of X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:307200; also known as agammaglobulinemia and isolated growth hormone deficiency or Fleisher syndrome or isolated growth hormone deficiency type 3 (IGHD3). In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD).
Function
BTK_HUMAN Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. 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.[25] [26] [27] [28] [29] [30]
Publication Abstract from PubMed
Bruton tyrosine kinase (BTK) is essential for B-cell receptor (BCR) signaling, a driver of chronic lymphocytic leukemia (CLL). Covalent inhibitors bind C481 in the active site of BTK and have become a preferred CLL therapy. Disease progression on covalent BTK inhibitors is commonly associated with C481 mutations. Here, we investigated a targeted protein degrader, NRX-0492, that links a non-covalent BTK binding domain to cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NRX-0492 selectively catalyzes ubiquitylation and proteasomal degradation of BTK. In primary CLL cells, NRX-0492 induced rapid and sustained degradation of both wild-type and C481 mutant BTK at half maximal degradation concentration (DC50) of </=0.2 nM and DC90 of </=0.5 nM, respectively. Sustained degrader activity was maintained for at least 24 hours after washout and was equally observed in high-risk (deletion 17p) and standard-risk (deletion 13q only) CLL subtypes. In in vitro testing against treatment-naive CLL samples, NRX-0492 was as effective as ibrutinib at inhibiting BCR mediated signaling, transcriptional programs, and chemokine secretion. In patient-derived xenografts, orally administered NRX-0492 induced BTK degradation and inhibited activation and proliferation of CLL cells in blood and spleen and remained efficacious against primary C481S mutant CLL cells collected from a patient progressing on ibrutinib. Oral bioavailability, >90% degradation of BTK at sub-nanomolar concentrations and sustained pharmacodynamic effects after drug clearance make this class of targeted protein degraders uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022).
NRX-0492 Degrades Wildtype and C481 Mutant BTK and Demonstrates in vivo Activity in CLL Patient Derived Xenografts.,Zhang D, Harris HM, Chen J, Judy JT, James G, Kelly A, McIntosh J, Tenn-McClellan A, Ambing ER, Tan YS, Lu H, Gajewski S, Clifton MC, Yung S, Robbins DW, Piroozia M, Skanland SS, Gaglione EM, Mhibik M, Underbayev C, Ahn I, Sun C, Herman SEM, Noviski MA, Wiestner A Blood. 2022 Nov 14:blood.2022016934. doi: 10.1182/blood.2022016934. PMID:36375120 [31]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hagemann TL, Chen Y, Rosen FS, Kwan SP. Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia. Hum Mol Genet. 1994 Oct;3(10):1743-9. PMID:7880320
- ↑ Duriez B, Duquesnoy P, Dastot F, Bougneres P, Amselem S, Goossens M. An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency. FEBS Lett. 1994 Jun 13;346(2-3):165-70. PMID:8013627
- ↑ Bradley LA, Sweatman AK, Lovering RC, Jones AM, Morgan G, Levinsky RJ, Kinnon C. Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis. Hum Mol Genet. 1994 Jan;3(1):79-83. PMID:8162056
- ↑ de Weers M, Mensink RG, Kraakman ME, Schuurman RK, Hendriks RW. Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice. Hum Mol Genet. 1994 Jan;3(1):161-6. PMID:8162018
- ↑ Conley ME, Fitch-Hilgenberg ME, Cleveland JL, Parolini O, Rohrer J. Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase. Hum Mol Genet. 1994 Oct;3(10):1751-6. PMID:7849697
- ↑ Zhu Q, Zhang M, Winkelstein J, Chen SH, Ochs HD. Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families. Hum Mol Genet. 1994 Oct;3(10):1899-900. PMID:7849721
- ↑ Vihinen M, Vetrie D, Maniar HS, Ochs HD, Zhu Q, Vorechovsky I, Webster AD, Notarangelo LD, Nilsson L, Sowadski JM, et al.. Structural basis for chromosome X-linked agammaglobulinemia: a tyrosine kinase disease. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12803-7. PMID:7809124
- ↑ Vihinen M, Zvelebil MJ, Zhu Q, Brooimans RA, Ochs HD, Zegers BJ, Nilsson L, Waterfield MD, Smith CI. Structural basis for pleckstrin homology domain mutations in X-linked agammaglobulinemia. Biochemistry. 1995 Feb 7;34(5):1475-81. PMID:7849006
- ↑ Vorechovsky I, Vihinen M, de Saint Basile G, Honsova S, Hammarstrom L, Muller S, Nilsson L, Fischer A, Smith CI. DNA-based mutation analysis of Bruton's tyrosine kinase gene in patients with X-linked agammaglobulinaemia. Hum Mol Genet. 1995 Jan;4(1):51-8. PMID:7711734
- ↑ Jin H, Webster AD, Vihinen M, Sideras P, Vorechovsky I, Hammarstrom L, Bernatowska-Matuszkiewicz E, Smith CI, Bobrow M, Vetrie D. Identification of Btk mutations in 20 unrelated patients with X-linked agammaglobulinaemia (XLA). Hum Mol Genet. 1995 Apr;4(4):693-700. PMID:7633420
- ↑ Gaspar HB, Bradley LA, Katz F, Lovering RC, Roifman CM, Morgan G, Levinsky RJ, Kinnon C. Mutation analysis in Bruton's tyrosine kinase, the X-linked agammaglobulinaemia gene, including identification of an insertional hotspot. Hum Mol Genet. 1995 Apr;4(4):755-7. PMID:7633429
- ↑ Vorechovsky I, Luo L, de Saint Basile G, Hammarstrom L, Webster AD, Smith CI. Improved oligonucleotide primer set for molecular diagnosis of X-linked agammaglobulinaemia: predominance of amino acid substitutions in the catalytic domain of Bruton's tyrosine kinase. Hum Mol Genet. 1995 Dec;4(12):2403-5. PMID:8634718
- ↑ Hagemann TL, Rosen FS, Kwan SP. Characterization of germline mutations of the gene encoding Bruton's tyrosine kinase in families with X-linked agammaglobulinemia. Hum Mutat. 1995;5(4):296-302. PMID:7627183 doi:http://dx.doi.org/10.1002/humu.1380050405
- ↑ Ohashi Y, Tsuchiya S, Konno T. A new point mutation involving a highly conserved leucine in the Btk SH2 domain in a family with X linked agammaglobulinaemia. J Med Genet. 1995 Jan;32(1):77-8. PMID:7897635
- ↑ Schuster V, Seidenspinner S, Kreth HW. Detection of a novel mutation in the SRC homology domain 2 (SH2) of Bruton's tyrosine kinase and direct female carrier evaluation in a family with X-linked agammaglobulinemia. Am J Med Genet. 1996 May 3;63(1):318-22. PMID:8723128 doi:<318::AID-AJMG53>3.0.CO;2-N 10.1002/(SICI)1096-8628(19960503)63:1<318::AID-AJMG53>3.0.CO;2-N
- ↑ Hashimoto S, Tsukada S, Matsushita M, Miyawaki T, Niida Y, Yachie A, Kobayashi S, Iwata T, Hayakawa H, Matsuoka H, Tsuge I, Yamadori T, Kunikata T, Arai S, Yoshizaki K, Taniguchi N, Kishimoto T. Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan. Blood. 1996 Jul 15;88(2):561-73. PMID:8695804
- ↑ Kobayashi S, Iwata T, Saito M, Iwasaki R, Matsumoto H, Naritaka S, Kono Y, Hayashi Y. Mutations of the Btk gene in 12 unrelated families with X-linked agammaglobulinemia in Japan. Hum Genet. 1996 Apr;97(4):424-30. PMID:8834236
- ↑ Vihinen M, Nore BF, Mattsson PT, Backesjo CM, Nars M, Koutaniemi S, Watanabe C, Lester T, Jones A, Ochs HD, Smith CI. Missense mutations affecting a conserved cysteine pair in the TH domain of Btk. FEBS Lett. 1997 Aug 18;413(2):205-10. PMID:9280283
- ↑ Saha BK, Curtis SK, Vogler LB, Vihinen M. Molecular and structural characterization of five novel mutations in the Bruton's tyrosine kinase gene from patients with X-linked agammaglobulinemia. Mol Med. 1997 Jul;3(7):477-85. PMID:9260159
- ↑ Conley ME, Mathias D, Treadaway J, Minegishi Y, Rohrer J. Mutations in btk in patients with presumed X-linked agammaglobulinemia. Am J Hum Genet. 1998 May;62(5):1034-43. PMID:9545398 doi:S0002-9297(07)61523-7
- ↑ Holinski-Feder E, Weiss M, Brandau O, Jedele KB, Nore B, Backesjo CM, Vihinen M, Hubbard SR, Belohradsky BH, Smith CI, Meindl A. Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course. Pediatrics. 1998 Feb;101(2):276-84. PMID:9445504
- ↑ Vihinen M, Kwan SP, Lester T, Ochs HD, Resnick I, Valiaho J, Conley ME, Smith CI. Mutations of the human BTK gene coding for bruton tyrosine kinase in X-linked agammaglobulinemia. Hum Mutat. 1999;13(4):280-5. PMID:10220140 doi:<280::AID-HUMU3>3.0.CO;2-L 10.1002/(SICI)1098-1004(1999)13:4<280::AID-HUMU3>3.0.CO;2-L
- ↑ Curtis SK, Hebert MD, Saha BK. Twin carriers of X-linked agammaglobulinemia (XLA) due to germline mutation in the Btk gene. Am J Med Genet. 2000 Jan 31;90(3):229-32. PMID:10678660
- ↑ Orlandi P, Ritis K, Moschese V, Angelini F, Arvanitidis K, Speletas M, Sideras P, Plebani A, Rossi P. Identification of nine novel mutations in the Bruton's tyrosine kinase gene in X-linked agammaglobulinaemia patients. Hum Mutat. 2000 Jan;15(1):117. PMID:10612838 doi:<117::AID-HUMU26>3.0.CO;2-H 10.1002/(SICI)1098-1004(200001)15:1<117::AID-HUMU26>3.0.CO;2-H
- ↑ Yang W, Desiderio S. BAP-135, a target for Bruton's tyrosine kinase in response to B cell receptor engagement. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):604-9. PMID:9012831
- ↑ Rodriguez R, Matsuda M, Perisic O, Bravo J, Paul A, Jones NP, Light Y, Swann K, Williams RL, Katan M. Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling. J Biol Chem. 2001 Dec 21;276(51):47982-92. Epub 2001 Oct 17. PMID:11606584 doi:10.1074/jbc.M107577200
- ↑ Horwood NJ, Page TH, McDaid JP, Palmer CD, Campbell J, Mahon T, Brennan FM, Webster D, Foxwell BM. Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production. J Immunol. 2006 Mar 15;176(6):3635-41. PMID:16517732
- ↑ Rajaiya J, Nixon JC, Ayers N, Desgranges ZP, Roy AL, Webb CF. Induction of immunoglobulin heavy-chain transcription through the transcription factor Bright requires TFII-I. Mol Cell Biol. 2006 Jun;26(12):4758-68. PMID:16738337 doi:10.1128/MCB.02009-05
- ↑ Mansell A, Smith R, Doyle SL, Gray P, Fenner JE, Crack PJ, Nicholson SE, Hilton DJ, O'Neill LA, Hertzog PJ. Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol. 2006 Feb;7(2):148-55. Epub 2006 Jan 15. PMID:16415872 doi:10.1038/ni1299
- ↑ Doyle SL, Jefferies CA, Feighery C, O'Neill LA. Signaling by Toll-like receptors 8 and 9 requires Bruton's tyrosine kinase. J Biol Chem. 2007 Dec 21;282(51):36953-60. Epub 2007 Oct 11. PMID:17932028 doi:10.1074/jbc.M707682200
- ↑ Zhang D, Harris HM, Chen J, Judy J, James G, Kelly A, McIntosh J, Tenn-McClellan A, Ambing E, Tan YS, Lu H, Gajewski S, Clifton MC, Yung S, Robbins DW, Pirooznia M, Skånland SS, Gaglione E, Mhibik M, Underbayev C, Ahn IE, Sun C, Herman SEM, Noviski M, Wiestner A. NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts. Blood. 2023 Mar 30;141(13):1584-1596. PMID:36375120 doi:10.1182/blood.2022016934
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