Bruton's tyrosine kinase (BTK) is a key component of B cell receptor (BCR) signalling and functions as an important regulator of cell proliferation and cell survival in various B cell malignancies. Small-molecule inhibitors of BTK have shown antitumour activity in animal models and, recently, in clinical studies. High response rates were reported in patients with chronic lymphocytic leukaemia and mantle cell lymphoma. Remarkably, BTK inhibitors have molecular effects that cannot be explained by the classic role of BTK in BCR signalling. In this Review, we highlight the importance of BTK in various signalling pathways in the context of its therapeutic inhibition.

/pdf/targeting-bruton-s-tyrosine-kinase-in-b-cell-malignancies-mf0ddw583x.pdf

Targeting Bruton's tyrosine kinase in B cell malignancies

Drug metabolism in drug discovery and development

Adaptive humoral immune responses in the airways are mediated by B cells and plasma cells that express highly evolved and specific receptors and produce immunoglobulins of most isotypes. In some cases, such as autoimmune diseases or inflammatory diseases caused by excessive exposure to foreign antigens, these same immune cells can cause disease by virtue of overly vigorous responses. This review discusses the generation, differentiation, signaling, activation, and recruitment pathways of B cells and plasma cells, with special emphasis on unique characteristics of subsets of these cells functioning within the respiratory system. The primary sensitization events that generate B cells responsible for effector responses throughout the airways usually occur in the upper airways, tonsils, and adenoid structures that make up the Waldeyer ring. On secondary exposure to antigen in the airways, antigen-processing dendritic cells migrate into secondary lymphoid organs, such as lymph nodes, that drain the upper and lower airways, and further B-cell expansion takes place at those sites. Antigen exposure in the upper or lower airways can also drive expansion of B-lineage cells in the airway mucosal tissue and lead to the formation of inducible lymphoid follicles or aggregates that can mediate local immunity or disease.

/pdf/b-lymphocyte-lineage-cells-and-the-respiratory-system-1jd5wp5azw.pdf

B-lymphocyte lineage cells and the respiratory system.

In recent years, claims of increased involvement of non-cytochrome P450 (non-P450) enzymes in the metabolism of drugs have appeared in the literature. However, no temporal summaries of the contribution of non-P450 enzymes to the metabolism of drugs have been published. Using data from human radiolabeled absorption, distribution, metabolism, and excretion studies available for a set of 125 orally or intravenously administered small-molecule drugs approved by the United States Food and Drug Administration from 2006 to 2015, the contributions of P450 and non-P450 enzymes to the formation of major metabolites (≥10% of dose) were assessed and tabulated. Over this time frame, the involvement of P450 versus non-P450 enzymes in the formation of major metabolites is compared, and the individual non-P450 enzymes responsible are described. This analysis indicates that non-P450 enzymes contribute significantly to the metabolism of the 125 drugs analyzed. Approximately 30% of the metabolism of these drugs is carried out by non-P450 enzymes, with the predominant non-P450 enzymes identified being glucuronosyltransferases (11.7%), hydrolases (10.8%), carbonyl reductases (2.4%), and aldehyde oxidase (1.1%). Although significant, the relative contribution of non-P450 enzymes to drug metabolism does not appear to have increased dramatically over the last 10 years. As the current evaluation involves drugs which emerged from the discovery phase >10 years ago, this evaluation may not reflect the current or evolving situation in some research organizations; therefore, additional monitoring and assessment of the involvement of non-P450 enzymes in the metabolism of drugs will be conducted in the future.

https://dmd.aspetjournals.org/content/dmd/44/8/1246.full.pdf

Prevalence of Non–Cytochrome P450–Mediated Metabolism in Food and Drug Administration–Approved Oral and Intravenous Drugs: 2006–2015

Since the original identification of Bruton’s tyrosine kinase (BTK) as the gene defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) in 1993, our knowledge on the physiological function of BTK has expanded impressively. In this review, we focus on the role of BTK during B cell differentiation in vivo, both in the regulation of expansion and in the developmental progression of pre-B cells in the bone marrow and as a crucial signal transducer of signals downstream of the IgM or IgG B cell antigen receptor (BCR) in mature B cells governing proliferation, survival, and differentiation. In particular, we highlight BTK function in B cells in the context of host defense and autoimmunity. Small-molecule inhibitors of BTK have very recently shown impressive anti-tumor activity in clinical studies in patients with various B cell malignancies. Since promising effects of BTK inhibition were also seen in experimental animal models for lupus and rheumatoid arthritis, BTK may be a good target for controlling autoreactive B cells in patients with systemic autoimmune disease.

BTK Signaling in B Cell Differentiation and Autoimmunity

(R)-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (GDC-0834) is a potent and selective inhibitor of Bruton's tyrosine kinase (BTK), investigated as a potential treatment for rheumatoid arthritis. In vitro metabolite identification studies in hepatocytes revealed predominant formation of an inactive metabolite (M1) via amide hydrolysis in human. The formation of M1 appeared to be NADPH-independent in human liver microsomes. M1 was found in only minor to moderate quantities in plasma from preclinical species dosed with GDC-0834. Human clearance predictions using various methodologies resulted in estimates ranging from low to high. In addition, GDC-0834 exhibited low clearance in PXB chimeric mice with humanized liver. Uncertainty in human pharmacokinetic prediction and high interest in a BTK inhibitor for clinical evaluation prompted an investigational new drug strategy, in which GDC-0834 was rapidly advanced to a single-dose human clinical trial. GDC-0834 plasma concentrations in humans were below the limit of quantitation (<1 ng/ml) in most samples from the cohorts dosed orally at 35 and 105 mg. In contrast, substantial plasma concentrations of M1 were observed. In human plasma and urine, only M1 and its sequential metabolites were identified. The formation kinetics of M1 was evaluated in rat, dog, monkey, and human liver microsomes in the absence of NADPH. The maximum rate of M1 formation (V(max)) was substantially higher in human compared with that in other species. In contrast, the Michaelis-Menten constant (K(m)) was comparable among species. Intrinsic clearance (V(max)/K(m)) of GDC-0834 from M1 formation in human was 23- to 169-fold higher than observed in rat, dog, and monkey.

https://dmd.aspetjournals.org/content/dmd/early/2011/07/08/dmd.111.040840.full.pdf

Significant Species Difference in Amide Hydrolysis of GDC-0834, a Novel Potent and Selective Bruton's Tyrosine Kinase Inhibitor

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Significant Species Difference in Amide Hydrolysis of GDC-0834, a Novel Potent and Selective Bruton's Tyrosine Kinase Inhibitor