BTK (Bruton tyrosine kinase)
The signalling enzyme that B-cell cancers use to survive. Blocking it turned chronic lymphocytic leukaemia into a disease controlled by a daily pill.
BTK sits downstream of the B-cell receptor. Covalent inhibitors (ibrutinib 2014, acalabrutinib, zanubrutinib) bind C481; resistance via C481S mutations is overcome by the non-covalent inhibitor pirtobrutinib (full approval December 2025) and, in phase 3, by BTK degraders (BGB-16673 vs pirtobrutinib in CaDAnCe-304). Standard in CLL, mantle cell lymphoma, Waldenström, and marginal zone lymphoma. Next-generation BTK inhibitors reduced the atrial fibrillation and bleeding seen with ibrutinib.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · The signalling enzyme that B-cell cancers use to survive. Blocking it turned chronic lymphocytic leukaemia into a disease controlled by a daily pill.
- 1 · What it is
The signalling enzyme that B-cell cancers use to survive. Blocking it turned chronic lymphocytic leukaemia into a disease controlled by a daily pill.
- 2 · What goes wrong in cancer
TEC-family cytoplasmic tyrosine kinase; phosphorylates PLCγ2 after BCR engagement. Resistance mutations: C481S/R/F (covalent), T474I and L528W (non-covalent, also confer cross-resistance).
- 3 · How drugs use it
6 products aim at BTK (Bruton tyrosine kinase): small molecules and degraders. Kinases are switched on by binding ATP inside the cell, so most drugs are small molecules shaped to plug that ATP pocket.
Biology
TEC-family cytoplasmic tyrosine kinase; phosphorylates PLCγ2 after BCR engagement. Resistance mutations: C481S/R/F (covalent), T474I and L528W (non-covalent, also confer cross-resistance).
- CLL/SLL
- Mantle cell lymphoma
- Waldenström macroglobulinaemia
- Marginal zone lymphoma
How common it is, by cancer
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Chronic lymphocytic leukaemia | 100% | pathway dependence (BCR signalling), not a mutation | Target is wild-type; resistance mutations arise on treatment |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Acalabrutinib is a cleaner BTK blocker with fewer heart and bleeding problems than ibrutinib. In February 2026 it became half of the first all-oral, fixed-duration CLL regimen.
Instead of blocking BTK, this pill destroys it, so it works even when the enzyme has mutated to escape every inhibitor.
The pill that ended chemotherapy for most CLL. It blocks the survival signal B cells depend on, and it was the first drug to beat chemoimmunotherapy in nearly every CLL setting.
Nemtabrutinib is Merck's reversible BTK blocker, active against the C481S escape mutation, being tested against ibrutinib and acalabrutinib in first-line CLL.
A BTK blocker that works after the older ones stop, because it grips a different part of the enzyme. Fully approved for CLL in December 2025.
Zanubrutinib is the only BTK blocker to beat ibrutinib on both efficacy and safety in a head-to-head trial. It is now the most prescribed BTK inhibitor in CLL.
AMPLIFY delivered the first all-oral, fixed-duration doublet for front-line CLL and supported its approval, giving fit patients a way to avoid both chemotherapy and years of continuous BTK inhibitor. It does not settle whether a doublet or triplet is best, or how AV compares with venetoclax-obinutuzumab. Patients with TP53 aberration were excluded and still need different strategies.
ELEVATE-TN put a more selective BTK inhibitor into first-line CLL and, with the head-to-head ELEVATE-RR trial, showed it is as effective as ibrutinib with fewer cardiac side effects. Continuous acalabrutinib became one of the two main front-line options alongside fixed-duration venetoclax combinations. The trade-off is indefinite therapy and cost versus a time-limited course.
ZUMA-2 gave patients with BTK-inhibitor-refractory mantle cell lymphoma, who previously had a median survival under a year, a therapy with durable remissions in a substantial fraction. Brexu-cel is now standard after BTK inhibitor failure and CAR-T is being tested earlier in the disease. Neurotoxicity rates are higher than in other lymphoma CAR-T trials.
Latest papers
topQuery for this target: (TITLE:"BTK" OR ABSTRACT:"BTK" OR TITLE:"Bruton tyrosine kinase" OR ABSTRACT:"Bruton tyrosine kinase") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about BTK (Bruton tyrosine kinase), not a curated reading list.
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