The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) regulates nuclear-factor-kappa-B (NF-κB) activation downstream of surface receptors with immunoreceptor tyrosine-based activation motifs (ITAMs), such as the B-cell or Tcell receptor and has thus emerged as a therapeutic target for autoimmune diseases. However, recent reports demonstrate the development of lethal autoimmune inflammation due to the excessive production of interferon gamma (IFN-ɣ) and defective differentiation of regulatory T-cells in genetically modified mice deficient in MALT1 paracaspase activity. To address this issue, we explored the effects of pharmacological MALT1 inhibition on the balance between T-effector and regulatory T-cells. Here we demonstrate that allosteric inhibition of MALT1 suppressed Th1, Th17 and Th1/Th17 effector responses, and inhibited T-cell dependent B-cell proliferation and antibody production. Allosteric MALT1 inhibition did not interfere with the suppressive function of human T-regulatory cells, although it impaired de novo differentiation of regulatory T-cells from naïve T-cells. Treatment with an allosteric MALT1 inhibitor alleviated the cytokine storm, including IFN-ɣ, in a mouse model of acute Tcell activation, and long-term treatment did not lead to an increase in IFN-ɣ producing CD4 cells or tissue inflammation. Together, our data demonstrate that the effects of allosteric inhibition of MALT1 differ from those seen in mice with proteolytically inactive MALT1, and thus we believe that MALT1 is a viable target for B and T-cell driven autoimmune diseases.
This paper describes the application of in vivo systems response profiling in CNS drug discovery by a process referred to as the Integrative Screening Process. The biological response profile, treated as an array, is used as major outcome for selection of candidate drugs. Dose-response data, including ex vivo brain monoaminergic biomarkers and behavioral descriptors, are systematically collected and analyzed by principal component analysis (PCA) and partial least-squares (PLS) regression, yielding multivariate characterization across compounds. The approach is exemplified by assessing a new class of CNS active compounds, the dopidines, compared to other monoamine modulating compounds including antipsychotics, antidepressants, and procognitive agents. Dopidines display a distinct phenotypic profile which has prompted extensive further preclinical and clinical investigations. In summary, in vivo profiles of CNS compounds are mapped, based on dose response studies in the rat. Applying a systematic and standardized work-flow, a database of in vivo systems response profiles is compiled, enabling comparisons and classification. This creates a framework for translational mapping, a crucial component in CNS drug discovery.
While
bronchodilators and inhaled corticosteroids are the mainstay
of asthma treatment, up to 50% of asthmatics remain uncontrolled.
Many studies show that the cysteinyl leukotriene cascade remains highly
activated in some asthmatics, even those on high-dose inhaled or oral
corticosteroids. Hence, inhibition of the leukotriene C4 synthase
(LTC4S) enzyme could provide a new and differentiated core treatment
for patients with a highly activated cysteinyl leukotriene cascade.
Starting from a screening hit (3), a program to discover
oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic
acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE =
8.5), which displays nanomolar potency in cells (peripheral blood
mononuclear cell, IC50,free = 6.2 nM) and good in vivo
pharmacodynamics in a calcium ionophore-stimulated rat model after
oral dosing (in vivo, IC50,free = 34 nM). Compound 36 mitigates the GABA binding, hepatic toxicity signal, and
in vivo toxicology findings of an early lead compound 7 with a human dose predicted to be 30 mg once daily.
A series of 1-propyl-4-arylpiperidines were synthesized and their effects on the dopaminergic and serotonergic systems tested in vivo and in vitro. Scaffold jumping among five- and six-membered bicyclic aryl rings attached to the piperidine ring had a marked impact on these effects. Potent and selective dopamine D(2) receptor antagonists were generated from 3-indoles, 3-benzoisoxazoles, 3-benzimidazol-2-one, and 3-benzothiophenes. In contrast, 3-benzofuran was a potent and selective inhibitor of monoamine oxidase (MAO) A. The effects of the synthesized compounds on 3,4-dihydroxyphenylacetic acid (DOPAC) levels correlated very well with their affinity for dopamine D(2) receptors and MAO A. In the 4-arylpiperidine series, the most promising compound for development was the 6-chloro-3-(1-propyl-4-piperidyl)-1H-benzimidazol-2-one (19), which displayed typical dopamine D(2) receptor antagonist properties in vivo but produced only a partial reduction on spontaneous locomotor activity. This indicates that the compound may have a lower propensity to induce parkinsonism in patients.
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