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Agents that Target Disease Pathways >  BtK Inhibitors

Last update: 08/02/2017

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What is Bruton's tyrosine kinase (BTK)?

As we understand it, Bruton's tyrosine kinase (Btk) is a pathway that controls the function of the B cell antigen receptor (BCR), the "business end" of the mature b-cell

The BCR is the receptor that binds to pathogens (bacteria, virus ...) that invade the body. In a sense, the BCR is the b-cell's reason for being ... what it does for a living.   Picture it:

In the illustration, the Ag represents an antigen bound to the B-Cell Receptor, and the Bruton's tyrosine kinase (Btk) is downstream of this molecule.

When the b-cell antigen receptor binds to an antigen a cascade of signals take place within the cell, which promotes the prolonged survival of the cell and cell cycle progression.  (Just what we don't want to happen when the b-cell is abnormal - a lymphoma cell.)

Drugs that bind to BTK may preferentially target mature b-cells (not skin cells, etc) preventing the BCR from working, and in turn limiting the survival of these cells.

Thus, btk-inhibitors may prove to be another important way to manage b-cell lymphoma, or improve the cure rate, with less toxicity than less-specific chemotherapy drugs.  The BTK inhibitors may be used as a single agent or with standard therapies -- similar to how Rituxan is used today.

Abstract Title: Regulation of B lymphocyte development and activation by Bruton's tyrosine kinase 

Agents targeting btk in clinical phase testing   

btk / B-cell receptor pathway
Ibrutinib (all - recent approval for CLL; inhibiting btk - on b-cell receptor pathway) Find trials
Ibrutinib for Lymphoma only  Find Trials
Acalabrutinib (ACP-196)  Find trials ASH15 Report


In the News

Acalabrutinib received an FDA breakthrough designation for the treatment of Mantle Cell Lymphoma.

This designation is given when "preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development."

Hereís the (no-longer recruiting) study thatís the likely basis for the breakthrough designation: 

Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor | Journal of Hematology & Oncology | Full Text 

"Acalabrutinib (ACP-196) is a novel irreversible second-generation BTK inhibitor that was shown to be more potent and selective than ibrutinib. This review summarized the preclinical research and clinical data of acalabrutinib."

Comment: Acalabrutinib is in the same class as Ibrutinib (similar target, also an oral drug). Ibrutinib is already approved for use in MCL. So we might safely assume that the efficacy and/or safety appears to be substantially better for Acalabrutinib. However, I could not find an published reports on outcomes in the trial above - nor a statement by FDA on the basis for the decision. In any case, it's very big and good news.

Fact Sheet: FDA Breakthrough Therapies 
2015: Experts discuss Initiation and Discontinuation of Ibrutinib From
* Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes 

This technical paper describes an off-target effect of ibrutinib that could, possibly, limit its long term use (as noted by Dr. Bryd in the discussion that follows). The off-target effect on t-cells might also further explain its efficacy as touched on in this snip:

This report establishes a previously unidentified immunomodulatory mechanism of action for ibrutinib that has the potential to expand its antitumor applications. Aside from T-cell malignancies for which ITK acts as a driver, it is well appreciated that tumors develop a prosurvival niche enhanced by Th2-polarized CD4 T cells.1,2 In leukemia, these cells provide constitutive IL-4, IL-6, and CD40L stimulation, driving the expansion of disease.44
* ASH 2012 Paper:
The Brutonís Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma
* Approval for CLL -  Medscape 2014:
FDA Sends Valentine to CLL Patients (Cheson video)
* Patient Power 2013:   Video of Dr Sharman discussing Ibrutinib and other options
Promising Advances in Treating Mantle Cell Lymphoma

* Dr Sharman 2013:
Ibrutinib gets first approval in Mantle Cell Lymphoma

*Onclive 2013:
FDA Approves Ibrutinib for Mantle Cell Lymphoma

*The Street 2013
Pharmacyclics' Lymphoma Drug Receives FDA Approval. Cost: $130,000 Per Year!
* Picture it:  B-cell receptor and related pathways:



Find Clinical reports:


Google Scholar Search on Btk inhibitors

Lymphomas that arise from mature B-cells


B-cells arise from stem cells in the bone marrow.  These specialized immune cells express different features as they mature (on there cell surface, but also internally). 

This provides opportunities to target lymphomas that arise from defective mature b-cells (such as follicular and DLBCL).   Therapy that binds such targets will not affect stem cells or immature b-cells - allowing for the restoration of this part of the immune system when the therapy is discontinued. 

Rituxan is an example of a therapy that is specific to mature b-cells, as it targets cd20, which is not expressed on immature b-cells as shown in the image that follows:


Picture it:  b-cell maturation on

In the illustration, the arrows show where CD20 and other surface markers on mature b-cells are first expressed.

Clinical trials for PCI-32765
(Ibrutinib) targeting Bruton's tyrosine (Btk):


Related Articles and information:

* Ibrutinib: full prescribing information (Label)
Immunology: 3.2.1 Stages of B lymphocytes maturation
Combined deficiencies in Bruton tyrosine kinase and phospholipase Cγ2 arrest B-cell development at a pre-BCR+ stage

Disclaimer:  The information on is not intended to be a substitute for 
professional medical advice or to replace your relationship with a physician.
For all medical concerns, you should always consult your doctor. 
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