1,665 results match your criteria bruton's tyrosine

Targeting Bruton's Tyrosine Kinase in Inflammatory and Autoimmune Pathologies.

Front Cell Dev Biol 2021 4;9:668131. Epub 2021 Jun 4.

Department of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands.

Bruton's tyrosine kinase (BTK) was discovered due to its importance in B cell development, and it has a critical role in signal transduction downstream of the B cell receptor (BCR). Targeting of BTK with small molecule inhibitors has proven to be efficacious in several B cell malignancies. Interestingly, recent studies reveal increased BTK protein expression in circulating resting B cells of patients with systemic autoimmune disease (AID) compared with healthy controls. Read More

View Article and Full-Text PDF

MOG autoantibodies trigger a tightly-controlled FcR and BTK-driven microglia proliferative response.

Brain 2021 Jun 18. Epub 2021 Jun 18.

Multiple Sclerosis and Neurorepair Research Unit, Biogen, Cambridge, USA.

Autoantibodies are a hallmark of numerous neurologic disorders, including multiple sclerosis (MS), autoimmune encephalitides and neuromyelitis optica (NMO). While well understood in peripheral myeloid cells, the pathophysiological significance of autoantibody-induced Fc receptor (FcR) signaling in microglia remains unknown, in part due to the lack of a robust in vivo model. Moreover, application of therapeutic antibodies for neurodegenerative disease also highlights the importance of understanding FcR signaling in microglia. Read More

View Article and Full-Text PDF

Next-generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells.

Clin Transl Immunology 2021 14;10(6):e1295. Epub 2021 Jun 14.

MS Development Unit Biogen Cambridge MA USA.

Objectives: Bruton's tyrosine kinase (BTK) plays a non-redundant signaling role downstream of the B-cell receptor (BCR) in B cells and the receptors for the Fc region of immunoglobulins (FcR) in myeloid cells. Here, we characterise BIIB091, a novel, potent, selective and reversible small-molecule inhibitor of BTK.

Methods: BIIB091 was evaluated and in preclinical models and in phase 1 clinical trial. Read More

View Article and Full-Text PDF

[Role of Bruton's tyrosine kinase in endotoxin/lipopolysaccharide-induced pyroptosis of intestinal cells in scalded mice].

Zhonghua Shao Shang Za Zhi 2021 May 31;37:1-9. Epub 2021 May 31.

Department of Burns, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.

To investigate the role of Bruton's tyrosine kinase (BTK) in pyroptosis of intestinal cells caused by endotoxin/lipopolysaccharide (LPS) in scalded mice. One hundred and twenty-eight male C57BL/6 mice aged 6-8 weeks were divided into sham injury group, scald alone group, scald+LPS group, scald+LPS+3 mg/kg LFM-A13 group, scald+LPS+10 mg/kg LFM-A13 group, and scald+LPS+30 mg/kg LFM-A13 group. There were 8 mice in sham injury group, and there were 24 mice in the other 5 groups, respectively. Read More

View Article and Full-Text PDF

BTK Promotes Atherosclerosis by Regulating Oxidative Stress, Mitochondrial Injury, and ER Stress of Macrophages.

Oxid Med Cell Longev 2021 27;2021:9972413. Epub 2021 May 27.

Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120.

Atherosclerosis (AS) is a chronic metabolic disease in arterial walls, characterized by lipid deposition and persistent aseptic inflammation. AS is regarded as the basis of a variety of cardiovascular and cerebrovascular diseases. It is widely acknowledged that macrophages would become foam cells after internalizing lipoprotein particles, which is an initial factor in atherogenesis. Read More

View Article and Full-Text PDF

A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment.

Front Oncol 2021 28;11:579488. Epub 2021 May 28.

Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.

Drug repositioning is a promising and powerful innovative strategy in the field of drug discovery. In this study, we screened a compound-library containing 800 Food and Drug Administration approved drugs for their anti-leukemic effect. All screening activities made use of human peripheral blood mononuclear cells (PBMCs), isolated from healthy or leukemic donors. Read More

View Article and Full-Text PDF

BCL-2 Inhibition as Treatment for Chronic Lymphocytic Leukemia.

Curr Treat Options Oncol 2021 Jun 10;22(8):66. Epub 2021 Jun 10.

Bone Marrow Transplantation Unit, Hospital Israelita Albert Einstein, Av. Albert Einstein (SP), São Paulo, 627/520, Brazil.

Opinion Statement: At the end of the 1990s, with the advent of imatinib for chronic myeloid leukemia and rituximab for B cell lymphoproliferative diseases with CD20 expression, there was a great conceptual evolution in the treatment of onco-hematological diseases. Researchers from around the world and the pharmaceutical industry began to focus their efforts on the so-called target therapy used alone or associated with classic chemotherapeutic drugs. In chronic lymphocytic leukemia, the development of second-generation anti-CD20 antibodies, biosimilars, PI3K (phosphatidylinositol 3-kinases) inhibitors, BTK (Bruton's tyrosine kinase) inhibitors, and anti-bcl 2 drugs represented mainly by venetoclax brought new, broader, and more effective opportunities in the treatment of this disease. Read More

View Article and Full-Text PDF

An Open-label, Single-arm, Multicenter Study of Ibrutinib in Japanese Patients With Steroid-dependent/Refractory Chronic Graft-Versus-Host Disease.

Transplant Cell Ther 2021 Jun 5. Epub 2021 Jun 5.

Janssen Pharmaceutical K.K., Tokyo, Japan.

Background: Chronic graft-versus-host disease (cGVHD) is a serious complication after allogeneic stem cell transplantation. There are no well-established treatment options for cGVHD after primary steroid-based treatment. Ibrutinib showed clinical benefit with an acceptable safety profile in steroid-dependent/refractory cGVHD patients in a Phase 1b/2 study (PCYC-1129-CA, NCT02195869), with which it was approved in the United States for adult cGVHD patients after failure of ≥1 systemic treatments. Read More

View Article and Full-Text PDF

Novel irreversible covalent BTK inhibitors discovered using DNA-encoded chemistry.

Bioorg Med Chem 2021 May 19;42:116223. Epub 2021 May 19.

X-Chem Inc., 100 Beaver Street, Waltham, MA 02453, USA. Electronic address:

Libraries of DNA-Encoded small molecules created using combinatorial chemistry and synthetic oligonucleotides are being applied to drug discovery projects across the pharmaceutical industry. The majority of reported projects describe the discovery of reversible, i.e. Read More

View Article and Full-Text PDF

Successful Management of a Patient with Refractory Primary Central Nervous System Lymphoma by Zanubrutinib.

Onco Targets Ther 2021 24;14:3367-3372. Epub 2021 May 24.

Department of Hematology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, People's Republic of China.

Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal non-Hodgkin lymphoma, and the most frequent histological type is diffuse large B-cell lymphoma (DLBCL). Bruton's tyrosine kinase inhibitor (BTKi) has shown clinical activity in DLBCL. We herein report a 53-year-old man who presented with binocular diplopia, gait instability, dizziness and bucking. Read More

View Article and Full-Text PDF

Aberrant B Cell Receptor Signaling in Naïve B Cells from Patients with Idiopathic Pulmonary Fibrosis.

Cells 2021 May 26;10(6). Epub 2021 May 26.

Department of Pulmonary Medicine, Erasmus MC, University Medical Center, 3015 GD Rotterdam, The Netherlands.

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease in which an impaired healing response to recurrent micro-injuries is thought to lead to fibrosis. Recent findings hint at a role for B cells and autoimmunity in IPF pathogenesis. We previously reported that circulating B cells from a fraction of patients, compared with healthy controls, express increased levels of the signaling molecule Bruton's tyrosine kinase (BTK). Read More

View Article and Full-Text PDF

Bruton's Tyrosine Kinase Targeting in Multiple Myeloma.

Int J Mol Sci 2021 May 27;22(11). Epub 2021 May 27.

Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA.

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. Read More

View Article and Full-Text PDF

Targeting BTK Signaling in the Microenvironment of Solid Tumors as a Feasible Cancer Therapy Option.

Cancers (Basel) 2021 May 3;13(9). Epub 2021 May 3.

Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA.

The cell environment plays a pivotal role in determining cellular outcome, as well as cancer initiation, progression, and dissemination. Within this environment, in addition to the structural components, such as the extracellular matrix, there are various types of cells surrounding the tumor cells. Communication among these cells and the tumor cells via signaling pathways is important for tumor growth. Read More

View Article and Full-Text PDF

Proteolysis Targeting Chimeras for BTK Efficiently Inhibit B-Cell Receptor Signaling and Can Overcome Ibrutinib Resistance in CLL Cells.

Front Oncol 2021 13;11:646971. Epub 2021 May 13.

Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.

Proteolysis targeting chimeras (PROTACs) are small molecules that form ternary complexes between their target and E3 ligase, resulting in ubiquitination and proteasomal degradation of the target protein. Using our own designed Bruton's tyrosine kinase (BTK) PROTAC compounds, we show herein efficient BTK degradation in chronic lymphocytic leukemia (CLL) cells. The reversible non-covalent compound (NC-1) was the most potent and therefore we focused on this PROTAC to investigate its subsequent effects on the BCR pathway. Read More

View Article and Full-Text PDF

Discovery of a Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase with Oral Anti-Inflammatory Activity.

ACS Med Chem Lett 2021 May 5;12(5):782-790. Epub 2021 Apr 5.

Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States.

Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Read More

View Article and Full-Text PDF

PROTAC-Mediated Degradation of Bruton's Tyrosine Kinase as a Therapeutic Strategy for Cancer.

Robert B Kargbo

ACS Med Chem Lett 2021 May 12;12(5):688-689. Epub 2021 Apr 12.

Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States.

View Article and Full-Text PDF

Zanubrutinib-induced liver injury: a case report and literature review.

BMC Gastroenterol 2021 May 29;21(1):244. Epub 2021 May 29.

Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.

Background: Zanubrutinib is a Bruton's tyrosine kinase inhibitor that has been recently licensed in refractory mantle cell lymphoma and under assessment in phase 3 clinical trials for other B cell malignancies. To date, there are no reported cases of hepatotoxicity secondary to zanubrutinib. We report the first case of severe liver injury due to zanubrutinib. Read More

View Article and Full-Text PDF

What Did Not Work: The Drug or the Trial?

Joan T Merrill

Arthritis Rheumatol 2021 May 27. Epub 2021 May 27.

Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK, 73104, USA.

In this issue of Arthritis & Rheumatology, the paper by Isenberg et al, entitled Efficacy, Safety, and Pharmacodynamic Effects of the Bruton's Tyrosine Kinase Inhibitor, Fenebrutinib (GDC-0853), in Systemic Lupus Erythematosus reports results of a Phase 2 trial of fenebrutinib, an inhibitor of Bruton's tyrosine kinase (BTK). This treatment met expected pharmacodynamic targets, decreasing phosphorylated BTK, dampening plasmablast signals, and lowering anti-dsDNA and IgG. No concerning safety signal was observed. Read More

View Article and Full-Text PDF

Efficacy, Safety, and Pharmacodynamic Effects of the Bruton's Tyrosine Kinase Inhibitor, Fenebrutinib (GDC-0853), in Systemic Lupus Erythematosus.

Arthritis Rheumatol 2021 May 27. Epub 2021 May 27.

Genentech, Inc, South San Francisco, CA, USA.

Background: Fenebrutinib (GDC-0853, FEN) is a non-covalent, oral, and highly selective inhibitor of Bruton's tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of FEN were assessed in this randomized, placebo-controlled, multi-center phase II study.

Methods: Patients with moderate-to-severely active systemic lupus erythematosus on background standard of care therapy were randomized to placebo, FEN 150 mg QD, or FEN 200 mg BID arms. Read More

View Article and Full-Text PDF

Successful treatment of "accelerated" chronic lymphocytic leukemia with single agent ibrutinib: A report of two cases.

Leuk Res Rep 2021 17;15:100247. Epub 2021 May 17.

Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA.

"Accelerated" chronic lymphocytic leukemia/small lymphocytic lymphoma (A-CLL) is a rare histological variant of CLL/SLL, which tends to exhibit an aggressive clinical behavior compared to CLL. Due to the rarity of A-CLL (<1% of all cases), the optimal management remains ill-defined. We report two cases of A-CLL from our institution, in which both relapsed following initial chemoimmunotherapy regimens. Read More

View Article and Full-Text PDF

Comparison of the drug-drug interactions potential of ibrutinib and acalabrutinib via inhibition of UDP-glucuronosyltransferase.

Toxicol Appl Pharmacol 2021 Aug 24;424:115595. Epub 2021 May 24.

School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China. Electronic address:

Ibrutinib and acalabrutinib are two Bruton's tyrosine kinase (BTK) inhibitors which have gained Food and Drug Administration (FDA) approval for the treatment of various B cell malignancies. Herein, we investigated the effects of the two drugs on UDP-glucuronosyltransferase (UGT) activities to evaluate their potential risk for drug-drug interactions (DDIs) via UGT inhibition. Our data indicated that ibrutinib exerted broad inhibition on most of UGTs, including a potent competitive inhibition against UGT1A1 with a K value of 0. Read More

View Article and Full-Text PDF

Ibrutinib reduces neutrophil infiltration, preserves neural tissue and enhances locomotor recovery in mouse contusion model of spinal cord injury.

Anat Cell Biol 2021 May 25. Epub 2021 May 25.

Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.

Following acute spinal cord injury (SCI), excessive recruitment of neutrophils can result in inflammation, neural tissue loss and exacerbation of neurological outcomes. Ibrutinib is a bruton's tyrosine kinase inhibitor in innate immune cells such as the neutrophils that diminishes their activation and influx to the site of injury. The present study evaluated the efficacy of ibrutinib administration in the acute phase of SCI on neural tissue preservation and locomotor recovery. Read More

View Article and Full-Text PDF

Frontline Treatment for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Targeted Therapy vs. Chemoimmunotherapy.

Sara Small Shuo Ma

Curr Hematol Malig Rep 2021 May 22. Epub 2021 May 22.

Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E Superior St, Lurie 3-103, Chicago, IL, 60611, USA.

Purpose Of Review: The treatment options for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have expanded significantly in the last few years, including the use of new classes of oral small molecular inhibitors targeting the B cell receptor signaling pathway or the apoptosis machinery. Targeted therapy with or without immunotherapy has quickly emerged as a new standard for frontline treatment of CLL/SLL, though the previous standard chemoimmunotherapy (CIT) remains a treatment option. In this review, we present data from key clinical trials to evaluate the benefits and risks associated with different frontline treatment approaches. Read More

View Article and Full-Text PDF

Screening and monitoring of the BTK mutation in a real-world cohort of patients with relapsed/refractory chronic lymphocytic leukaemia during ibrutinib therapy.

Br J Haematol 2021 May 21. Epub 2021 May 21.

Borsod-Abaúj-Zemplén County Hospital and University Teaching Hospital, Miskolc, Hungary.

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has revolutionised the therapeutic landscape of chronic lymphocytic leukaemia (CLL). Acquired mutations emerging at position C481 in the BTK tyrosine kinase domain are the predominant genetic alterations associated with secondary ibrutinib resistance. To assess the correlation between disease progression, and the emergence and temporal dynamics of the most common resistance mutation BTK , sensitive (10 ) time-resolved screening was performed in 83 relapsed/refractory CLL patients during single-agent ibrutinib treatment. Read More

View Article and Full-Text PDF

Diagnosis and Individualized Treatment of Secondary Central Nervous System Lymphoma: A Case Report.

Onco Targets Ther 2021 13;14:3167-3175. Epub 2021 May 13.

Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People's Republic of China.

Non-Hodgkin lymphoma can disseminate to the central nervous system at initiation of treatment for systemic lymphoma or spread during the relapse of systematic lymphoma with CNS involvement, which is defined as secondary central nervous system lymphoma (SCNSL). The incidence of SCNSL depends on the pathological type of lymphoma and is especially high in aggressive lymphoma. SCNSL has a poor prognosis because of the lack of effective treatment regimens. Read More

View Article and Full-Text PDF

Design and synthesis of novel substituted benzyl pyrrolopyrimidine derivatives as selective BTK inhibitors for treating mantle cell lymphoma.

Bioorg Chem 2021 Jul 7;112:104968. Epub 2021 May 7.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, PR China. Electronic address:

Ibrutinib, a potent irreversible Bruton's tyrosine kinase (BTK) inhibitor, was approved by the FDA for treating mantle cell lymphoma (MCL). Although ibrutinib exhibited excellent antitumor activity, it was associated with certain adverse reactions, with off-target effects against EGFR, Itk and Src family kinases. Our studies yielded a novel series of substituted benzyl pyrrolopyrimidine derivatives capable of potent inhibition of BTK. Read More

View Article and Full-Text PDF

Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations.

Chem Sci 2021 Jan 28;12(15):5511-5516. Epub 2021 Jan 28.

Centre for Computational Chemistry, School of Chemistry, University of Bristol Cantock's Close Bristol BS8 1TS UK

Ibrutinib is the first covalent inhibitor of Bruton's tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition will aid in the design of safer and more selective covalent inhibitors that target BTK. The mechanism of covalent inhibition in BTK has been uncertain because there is no appropriate residue nearby that can act as a base to deprotonate the cysteine thiol prior to covalent bond formation. Read More

View Article and Full-Text PDF
January 2021

Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension.

Thorax 2021 May 7. Epub 2021 May 7.

Department of Pulmonary Medicine, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands

Introduction: Autoreactivity against pulmonary vascular structures is thought to be involved in idiopathic pulmonary arterial hypertension (IPAH), but the underlying mechanisms remain poorly understood. We hypothesised that aberrant B-cell activation contributes to IPAH aetiology.

Methods: Mice with enhanced B-cell activation due to B-cell-specific overexpression of the B-cell receptor (BCR) signalling molecule Bruton's tyrosine kinase (BTK) were subjected to lung injury and examined for several pulmonary hypertension (PH) indices. Read More

View Article and Full-Text PDF

Integration of Metabolomics and Gene Expression Profiling Elucidates IL4I1 as Modulator of Ibrutinib Resistance in ABC-Diffuse Large B Cell Lymphoma.

Cancers (Basel) 2021 Apr 29;13(9). Epub 2021 Apr 29.

Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). B-cell NHLs rely on Bruton's tyrosine kinase (BTK) mediated B-cell receptor signaling for survival and disease progression. However, they are often resistant to BTK inhibitors or soon acquire resistance after drug exposure resulting in the drug-tolerant form. Read More

View Article and Full-Text PDF

Successful treatment of Epstein-Barr virus-associated primary central nervous system lymphoma due to post-transplantation lymphoproliferative disorder, with ibrutinib and third-party Epstein-Barr virus-specific T cells.

Am J Transplant 2021 May 4. Epub 2021 May 4.

Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia.

Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. Read More

View Article and Full-Text PDF