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Bruton's Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy.

ABSTRACT: B cells play a central role in the pathogenesis of multiple sclerosis (MS), as demonstrated through the success of various B cell-depleting monoclonal antibodies. Bruton's tyrosine kinase (BTK) is a critical molecule in intracellular signaling from the receptor of B cells and receptors expressed in the cells of the innate immune system. BTK inhibitors may be a non-cell-depleting alternative to B cell modulation. In this review, the structure, signaling, and roles of BTK are reviewed among the different inhibitors assayed in animal models of MS and clinical trials.

SUBMITTER: Garcia-Merino A

PROVIDER: S-EPMC8534278 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Bruton's Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy.

García-Merino Antonio A

Cells 20210927 10

B cells play a central role in the pathogenesis of multiple sclerosis (MS), as demonstrated through the success of various B cell-depleting monoclonal antibodies. Bruton's tyrosine kinase (BTK) is a critical molecule in intracellular signaling from the receptor of B cells and receptors expressed in the cells of the innate immune system. BTK inhibitors may be a non-cell-depleting alternative to B cell modulation. In this review, the structure, signaling, and roles of BTK are reviewed among the di ...[more]

PMID: 34685540

Similar Datasets

Bruton's tyrosine kinase inhibitors in the treatment of multiple sclerosis.

Project description:PurposeIn this review, we have highlighted a new class of drugs, Bruton's tyrosine kinase (BTK) inhibitors, and summarized the results of recent clinical trials in the treatment of multiple sclerosis.ViewsMultiple sclerosis (MS) is considered an autoimmune disease of the central nervous system, in which B-lymphocytes and myeloid cells, such as macrophages and microglia, play an important role in the pathogenesis. B-cells induce pathological processes by presenting autoantigens to T-lymphocytes, secreting pro-inflammatory cytokines, and forming ectopic lymphoid follicle-shaped clusters. Accordingly, the activation of microglia contributes to the development of chronic inflammation due to the production of chemokines, cytokines, reactive oxygen, and nitrogen species. BTK is an enzyme important in the activation and function of both B-lymphocytes and microglia. The demand for highly effective and well-tolerated drugs still remains at all stages of MS despite the availability of a number of effective drugs against the disease. Thus, in recent years BTK inhibitors have been the newest approach in the treatment of MS, since they affect the leading links of the pathogenesis of this disease and are able to pass through the blood-brain barrier.ConclusionsThe study of new mechanisms of the development of MS continues in combination with the elaboration of new treatment methods, i.e., Bruton's tyrosine kinase inhibitors. The review provided the analysis of core studies evaluating the safety and efficacy of these drugs. In the future, positive results of these studies will be able to greatly expand the therapy for various forms of MS.

| S-EPMC10243295 | biostudies-literature

Bruton's Tyrosine Kinase Inhibition in Multiple Sclerosis.

Project description:Purpose of reviewMultiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with a chronic and often progressive disease course. The current disease-modifying treatments (DMTs) limit disease progression primarily by dampening immune cell activity in the peripheral blood or hindering their migration from the periphery into the CNS. New therapies are needed to target CNS immunopathology, which is a key driver of disability progression in MS. This article reviews Bruton's Tyrosine Kinase Inhibitors (BTKIs), a new class of experimental therapy that is being intensely evaluated in MS. We focus on the potential peripheral and central mechanisms of action of BTKIs and their use in recent clinical trials in MS.Recent findingsThere is evidence that some BTKIs cross the blood-brain barrier and may be superior to currently available DMTs at dampening the chronic neuroinflammatory processes compartmentalized within the CNS that contribute to progressive worsening in people withMS (pwMS). Recently, evobrutinib and tolebrutinib have shown efficacy in phase II clinical trials, and there are numerous ongoing phase III clinical trials of various BTKIs in relapsing and progressive forms of MS. Results from these clinical trials will be essential to understand the efficacy and safety of BTKIs across the spectrum of MS and keydifferences between specific BTKIs when treating pwMS. Inhibition of BTK has emerged as an attractive strategy to target cells of the adaptive and innate immune system outside and within the CNS. BTKIs carry great therapeutic potential across the MS spectrum, where key pathobiology aspects seem confined to the CNS compartment.

| S-EPMC9607648 | biostudies-literature

Bruton's Tyrosine Kinase Inhibitors: The Next Frontier of B-Cell-Targeted Therapies for Cancer, Autoimmune Disorders, and Multiple Sclerosis.

Project description:Bruton's tyrosine kinase (BTK) is an important protein belonging to the tyrosine kinase family that plays a key role in the intracellular signaling and proliferation, migration, and survival of normal and malignant B-lymphocytes and myeloid cells. Understanding the role of BTK in the B-cell signaling pathway has led to the development of BTK inhibitors (BTKi) as effective therapies for malignancies of myeloid origin and exploration as a promising therapeutic option for other cancers. Given its central function in B-cell receptor signaling, inhibition of BTK is an attractive approach for the treatment of a wide variety of autoimmune diseases that involve aberrant B-cell function including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). Here, we review the role of BTK in different cell signaling pathways, the development of BTKi in B-cell malignancies, and their emerging role in the treatment of MS and other autoimmune disorders.

| S-EPMC9604914 | biostudies-literature

Bruton's Tyrosine Kinase Targeting in Multiple Myeloma.

Project description:Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones' hematopoiesis and microenvironment homeostasis and ability to mediate an immune response against malignant clones. Despite prominent survival improvement with newer treatment modalities since the 2000s, MM is still considered a non-curable disease. Patients experience disease recurrence episodes with clonal evolution, and with each relapse disease comes back with a more aggressive phenotype. Bruton's Tyrosine Kinase (BTK) has been a major target for B cell clonal disorders and its role in clonal plasma cell disorders is under active investigation. BTK is a cytosolic kinase which plays a major role in the immune system and its related malignancies. The BTK pathway has been shown to provide survival for malignant clone and multiple myeloma stem cells (MMSCs). BTK also regulates the malignant clones' interaction with the bone marrow microenvironment. Hence, BTK inhibition is a promising therapeutic strategy for MM patients. In this review, the role of BTK and its signal transduction pathways are outlined in the context of MM.

| S-EPMC8198777 | biostudies-literature

Novel Bruton's tyrosine kinase inhibitors currently in development.

Project description:Bruton's tyrosine kinase (Btk) is intimately involved in multiple signal-transduction pathways regulating survival, activation, proliferation, and differentiation of B-lineage lymphoid cells. Btk is overexpressed and constitutively active in several B-lineage lymphoid malignancies. Btk has emerged as a new antiapoptotic molecular target for treatment of B-lineage leukemias and lymphomas. Preclinical and early clinical results indicate that Btk inhibitors may be useful in the treatment of leukemias and lymphomas.

| S-EPMC3594038 | biostudies-literature

Promising Multiple Sclerosis Agents In Late-Stage Development.

Project description:Developing drugs with enhanced safety profiles and improving treatment affordability are vital for patients with MS. The author reviews some encouraging new agents in late-stage development.

| S-EPMC6281141 | biostudies-other

Novel Indications for Bruton's Tyrosine Kinase Inhibitors, beyond Hematological Malignancies.

Project description:Bruton's tyrosine kinase (BTK) is a critical terminal enzyme in the B-cell antigen receptor (BCR) pathway. BTK activation has been implicated in the pathogenesis of certain B-cell malignancies. Targeting this pathway has emerged as a novel target in B-cell malignancies, of which ibrutinib is the first-in-class agent. A few other BTK inhibitors (BTKi) are also under development (e.g., acalabrutinib). While the predominant action of BTKi is the blockade of B-cell receptor pathway within malignant B-cells, increasing the knowledge of off-target effects as well as a potential role for B-cells in proliferation of solid malignancies is expanding the indication of BTKi into non-hematological malignancies. In addition to the expansion of the role of BTKi monotherapy, combination therapy strategies utilizing ibrutinib with established regimens and combination with modern immunotherapy compounds are being explored.

| S-EPMC5920436 | biostudies-literature

Inhibitors targeting Bruton's tyrosine kinase in cancers: drug development advances.

Project description:Bruton's tyrosine kinase (BTK) inhibitor is a promising novel agent that has potential efficiency in B-cell malignancies. It took approximately 20 years from target discovery to new drug approval. The first-in-class drug ibrutinib creates possibilities for an era of chemotherapy-free management of B-cell malignancies, and it is so popular that gross sales have rapidly grown to more than 230 billion dollars in just 6 years, with annual sales exceeding 80 billion dollars; it also became one of the five top-selling medicines in the world. Numerous clinical trials of BTK inhibitors in cancers were initiated in the last decade, and ~73 trials were intensively announced or updated with extended follow-up data in the most recent 3 years. In this review, we summarized the significant milestones in the preclinical discovery and clinical development of BTK inhibitors to better understand the clinical and commercial potential as well as the directions being taken. Furthermore, it also contributes impactful lessons regarding the discovery and development of other novel therapies.

| S-EPMC7862069 | biostudies-literature

Bruton's Tyrosine Kinase Inhibitors Prevent Therapeutic Escape in Breast Cancer Cells.

Project description:We have reported that a novel isoform of BTK (BTK-C) expressed in breast cancer protects these cells from apoptosis. In this study, we show that recently developed inhibitors of BTK, such as ibrutinib (PCI-32765), AVL-292, and CGI-1746, reduce breast cancer cell survival and prevent drug-resistant clones from arising. Ibrutinib treatment impacts HER2(+) breast cancer cell viability at lower concentrations than the established breast cancer therapeutic lapatinib. In addition to inhibiting BTK, ibrutinib, but not AVL-292 and CGI-1746, efficiently blocks the activation of EGFR, HER2, ErbB3, and ErbB4. Consequently, the activation of AKT and ERK signaling pathways are also blocked leading to a G1-S cell-cycle delay and increased apoptosis. Importantly, inhibition of BTK prevents activation of the AKT signaling pathway by NRG or EGF that has been shown to promote growth factor-driven lapatinib resistance in HER2(+) breast cancer cells. HER2(+) breast cancer cell proliferation is blocked by ibrutinib even in the presence of these factors. AVL-292, which has no effect on EGFR family activation, prevents NRG- and EGF-dependent growth factor-driven resistance to lapatinib in HER2(+) breast cancer cells. In vivo, ibrutinib inhibits HER2(+) xenograft tumor growth. Consistent with this, immunofluorescence analysis of xenograft tumors shows that ibrutinib reduces the phosphorylation of HER2, BTK, Akt, and Erk and histone H3 and increases cleaved caspase-3 signals. As BTK-C and HER2 are often coexpressed in human breast cancers, these observations indicate that BTK-C is a potential therapeutic target and that ibrutinib could be an effective drug especially for HER2(+) breast cancer. Mol Cancer Ther; 15(9); 2198-208. ©2016 AACR.

| S-EPMC5145257 | biostudies-literature

The Use of Bruton's Tyrosine Kinase Inhibitors to Treat Allergic Disorders.

Project description:Purpose of reviewStudies show that inhibitors of Bruton's tyrosine kinase (BTKis), currently FDA-approved for the treatment of B cell malignancies, can prevent IgE-mediated reactions through broad inhibition of the FcεRI signaling pathway in human mast cells and basophils. This review will summarize recent data supporting the use of these drugs as novel therapies in various allergic disorders.Recent findingsRecent studies have shown that BTKis can prevent IgE-mediated degranulation and cytokine production in primary human mast cells and basophils. Two oral doses of the second-generation BTKi acalabrutinib can completely prevent moderate passive systemic anaphylaxis in humanized mice and even protect against death during severe anaphylaxis. Furthermore, two doses of ibrutinib can reduce or eliminate skin prick test responses to foods and aeroallergens in allergic subjects. BTKis in development also show efficacy in clinical trials for chronic urticaria. Unlike other therapies targeting IgE, such as omalizumab, BTKis appear to have rapid onset and transient effects, making them ideal candidates for intermittent use to prevent acute reactions such as IgE-mediated anaphylaxis.SummaryThese studies suggest that BTKis may be capable of preventing IgE-mediated anaphylaxis, paving the way for future trials in food allergy and urticaria.

| S-EPMC8050815 | biostudies-literature

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