Bruton's Tyrosine Kinase

Bruton's tyrosine kinase (abbreviated Btk or BTK), also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the ''BTK'' gene in humans. BTK plays a crucial role in B cell development.

Structure

BTK contains five different protein interaction domains. These domains include an amino terminal pleckstrin homology (PH) domain, a proline-rich TEC homology (TH) domain, SRC homology (SH) domains SH2 and SH3, as well as a protein kinase domain with tyrosine phosphorylation activity.
Part of the TH domain is folded against the PH domain while the rest is intrinsically disordered.

Function

BTK plays a crucial role in B cell development as it is required for transmitting signals from the pre-B cell receptor that forms after successful immunoglobulin heavy chain rearrangement. It also has a role in mast cell activation through the high-affinity IgE receptor.

BTK contains a PH domain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 binding induces BTK to phosphorylate phospholipase C (PLC), which in turn hydrolyzes PIP₂, a phosphatidylinositol, into two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which then go on to modulate the activity of downstream proteins during B-cell signalling.

Clinical significance

Mutations in the BTK gene are implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia); sometimes abbreviated to XLA and selective IgM deficiency. Patients with XLA have normal pre-B cell populations in their bone marrow but these cells fail to mature and enter the circulation. The BTK gene is located on the X chromosome (Xq21.3-q22).X-Linked Agammaglobulinemia
Patient and Family Handbook for The Primary Immune Diseases. Third Edition. 2001. Published by the Immune Deficiency Foundation. At least 400 mutations of the BTK gene have been identified. Of these, at least 212 are considered to be disease-causing mutations.

BTK is important for the survival and proliferation of leukemic B cells, which motivated efforts to develop BTK inhibitors as treatments for B cell malignancies such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). As BTK is also linked to autoimmune disorders, recent efforts have sought to evaluate BTK inhibition as a therapeutic strategy for treatment of diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA).

BTK inhibitors

Approved drugs that inhibit BTK:
* Ibrutinib (Imbruvica), a selective Bruton's tyrosine kinase inhibitor.
* Acalabrutinib (Calquence), approved in October 2017 for relapsed mantle cell lymphoma and in October 2019 for Chronic lymphocytic leukemia (CLL) and Small lymphocytic lymphoma (SLL)
* Zanubrutinib (Brukinsa) for mantle cell lymphoma, chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL). It can be taken by mouth.BeiGene Announces Initiation of a Combination Trial of the BTK Inhibitor BGB-3111 with the PD-1 Antibody BGB-A317. June 2016
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* Tirabrutinib (Velexbru), approved in March 2020, in Japan, for the treatment of recurrent or refractory primary central nervous system lymphoma.
* Pirtobrutinib (Jaypirca), a reversible (non-covalent) inhibitor of BTK, for mantle cell lymphoma.
* Orelabrutinib, approved in China for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL), who have received at least one treatment in the past.

Various drugs that inhibit BTK are in clinical trials:

* Phase 3:
** Evobrutinib for multiple sclerosis.
** Tolebrutinib, for multiple sclerosis.
** Remibrutinib, for multiple sclerosis.
** Fenebrutinib (RG7845) for multiple sclerosis.
* Rilzabrutinib

* Phase 2:
** ABBV-105 for systemic lupus erythematosus (SLE)
**Fenebrutinib (GDC-0853) for rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and chronic spontaneous urticaria.
* Phase 1:
** Tirabrutinib, for non-Hodgkin lymphoma and/or CLL. Renamed GS-4059 and now in trial NCT02457598.
** Spebrutinib (AVL-292, CC-292)
** HM71224, for autoimmune diseases, under development by Hanmi Pharmaceutical and Lilly as of 2015
** Luxeptinib (CG-806), for CLL, SLL, non-Hodgkin lymphoma, acute myeloid leukaemia, and myelodysplastic syndromes
Phase I TrialPhase I Trial
. The inhibitor targets multiple kinase pathways, including BTK and FLT3.
* Elsubrutinib
* Vecabrutinib
* Nemtabrutinib

Discovery

Bruton's tyrosine kinase is named for Ogden Bruton, who first described XLA in 1952. Later studies in 1993 and 1994 reported the discovery of BTK (initially termed B cell progenitor kinase or BPK) and found that BTK levels are reduced in B cells from XLA patients.

Interactions

Bruton's tyrosine kinase has been shown to interact with:

* ARID3A
* BLNK (SLP-65),
* CAV1,
* GNAQ,
* GTF2I,
* PLCG2,
* PRKD1, and
* SH3BP5.

References

Further reading

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External links

GeneReviews/NCBI/NIH/UW entry on X-Linked or Brunton's Agammaglobulinemia
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{{DEFAULTSORT:Bruton's Tyrosine Kinase
Peripheral membrane proteins
Tyrosine kinases