# 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 PIP$_2$, 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). 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.
* 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 Trial; Phase 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.