A5082992641- Chronic Lymphocytic Leukemia Research
- Chemical Synthesis and Analysis
- Synthetic Organic Chemistry Methods
- Chronic Myeloid Leukemia Treatments
- Immunodeficiency and Autoimmune Disorders
- Asymmetric Synthesis and Catalysis
- Lymphoma Diagnosis and Treatment
- Asymmetric Hydrogenation and Catalysis
- Click Chemistry and Applications
- Biochemical and Molecular Research
- Coordination Chemistry and Organometallics
- Protein Tyrosine Phosphatases
- Platelet Disorders and Treatments
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Multicomponent Synthesis of Heterocycles
- Cytokine Signaling Pathways and Interactions
- Oral and gingival health research
- Chemical Reaction Mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Protein Degradation and Inhibitors
- interferon and immune responses
- Immune Response and Inflammation
- Cyclopropane Reaction Mechanisms
- Amyotrophic Lateral Sclerosis Research
- Cancer-related gene regulation
Biogen (United States)
2010-2024
Infinity Pharmaceuticals (United States)
2006
Imperial College London
2001-2005
Abstract Bruton's tyrosine kinase (BTK), a member of the TEC family kinases, plays crucial role in B‐cell maturation and mast cell activation. Although structures unphosphorylated mouse BTK domain phosphorylated domains human ITK are known, understanding selectivity profiles inhibitors has been hampered by lack availability high resolution, ligand‐bound structure. Here, we report crystal bound to either Dasatinib (BMS‐354825) at 1.9 Å resolution or...
Abstract Inhibition of Bruton’s Tyrosine Kinase (BTKi) is now viewed as a promising next-generation B-cell-targeting therapy for autoimmune diseases including multiple sclerosis (MS). Surprisingly little known; however, about how BTKi influences MS disease-implicated functions B cells. Here, we demonstrate that in addition to its expected impact on B-cell activation, attenuates B-cell:T-cell interactions via novel mechanism involving modulation metabolic pathways which, turn, mediates an...
Interleukin receptor-associated kinase 4 (IRAK4) is a key node of signaling within the innate immune system that regulates production inflammatory cytokines and chemokines. The presence
Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), nonreceptor member of the TEC family kinases, involved in regulation, migration, functional activation B cells myeloid periphery central nervous system (CNS), cell types which are deemed to contributing progression MS patients. Herein, we describe discovery BIIB129 (25), structurally distinct...
Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In early stage MS, inflammation primary driver disease progression. There remains an unmet need develop high efficacy therapies with superior safety profiles prevent processes Herein, we describe discovery BIIB091, structurally distinct orthosteric ATP competitive, reversible inhibitor...
Autoreactive B cell-derived antibodies form immune complexes that likely play a pathogenic role in autoimmune diseases. In systemic lupus erythematosus (SLE), these bind Fc receptors on myeloid cells and induce proinflammatory cytokine production by monocytes NETosis neutrophils. Bruton's tyrosine kinase (BTK) is non-receptor signals downstream of plays transduction antibody expression following cell activation. Given the roles BTK both sensing autoreactive antibodies, inhibitors activity...
[reaction: see text] ROMPgel-supported triphenylphosphine was synthesized in three steps (67%) from norbornadiene, 4-bromoiodobenzene, and chlorodiphenylphosphine. The supported reagent has a high loading (2.5 mmol/g) favorable swelling properties organic solvents. It been utilized for the conversion of alcohols to halides, reduction ozonides, isomerization alpha,beta-acetylenic esters Staudinger reaction. In general, filtration resin reaction mixtures evaporation gave corresponding products...
Combining a phenotypic screen with chemoproteomics reveals CDK12 as potential therapeutic target to inhibit noncanonical NF-κB in inflammation and cancer.
Bruton's tyrosine kinase (BTK) plays a non-redundant signaling role downstream of the B-cell receptor (BCR) in B cells and receptors for Fc region immunoglobulins (FcR) myeloid cells. Here, we characterise BIIB091, novel, potent, selective reversible small-molecule inhibitor BTK.BIIB091 was evaluated vitro vivo preclinical models phase 1 clinical trial.In vitro, BIIB091 potently inhibited BTK-dependent proximal distal functional responses both with IC50s ranging from 3 to 106 nm, including...
ROMPgel-supported ethyl 1-diazo-2-oxopropylphosphonate has been prepared, and the supported reagent effectively employed in conversion of a variety aldehydes into terminal alkynes under mild reaction conditions. The influence cross-link structure, comonomers, polymer structure on efficiency examined.
Abstract Background and purpose: BTK mediates B-cell receptor signaling was validated as a target by the inhibitor ibrutinib in several malignancies, including mantle cell lymphoma chronic lymphocytic leukemia (CLL). However, patients may have or acquire resistance. Resistance mechanisms include mutation of cysteine active site that requires for covalent binding (C481). We identified characterized SNS-062, potent, noncovalent with activity towards harboring resistance mutations also inhibits...
Phospholipase D (PLD) is a phospholipase enzyme responsible for hydrolyzing phosphatidylcholine into the lipid signaling molecule, phosphatidic acid, and choline. From therapeutic perspective, PLD has been implicated in human cancer progression as well target neurodegenerative diseases, including Alzheimer's. Moreover, knockdown of rescues ALS phenotype multiple Drosophila models (amyotrophic lateral sclerosis) displays modest motor benefits an SOD1 mouse model. To further validate whether...
An operationally simple protocol has been discovered that couples primary or secondary amines with N-aryl-substituted lactams to deliver differentiated diamines in moderate high yields. The process allows for the partial reduction of a lactam presence Cp2ZrHCl (Schwartz's reagent), followed by reductive amination between resulting hemiaminal and amine. These reactions can be telescoped one-pot fashion significantly simplify operation. scope substituted various ring sizes was demonstrated...
Chemical process development efforts leading to multikilogram production of BIIB068 hemiadipate are discussed. Process optimization resulted in (1) removal transition metal from the process, (2) a streamlined with significantly improved overall yield, and (3) appropriate impurity control (including potential mutagenic impurities), which enabled delivery quality material for toxicology studies clinical trials.
Route evaluation, process development, and large-scale manufacturing of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1) are described. The improved route consists two linear chemical steps: oxidation 4-chloro-2-(methylthio)pyrimidine (11) to 4-chloro-2-(methylsulfonyl)pyrimidine (7) displacement the sulfonyl with N-(1-methyl-1H-pyrazol-4-yl)formamide (10) under basic conditions followed by in situ hydrolysis N-formyl intermediate deliver compound 1....
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