13 research outputs found
Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis
Recently,
we reported a novel role for KMO in the pathogenesis
of acute pancreatitis (AP). A number of inhibitors of kynurenine 3-monooxygenase
(KMO) have previously been described as potential treatments for neurodegenerative
conditions and particularly for Huntingtonâs disease. However,
the inhibitors reported to date have insufficient aqueous solubility
relative to their cellular potency to be compatible with the intravenous
(iv) dosing route required in AP. We have identified and optimized
a novel series of high affinity KMO inhibitors with favorable physicochemical
properties. The leading example is exquisitely selective, has low
clearance in two species, prevents lung and kidney damage in a rat
model of acute pancreatitis, and is progressing into preclinical development
Kynurenineâ3âmonooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis
Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death1,2 Acute mortality from AP-MODS exceeds 20%3 and for those who survive the initial episode, their lifespan is typically shorter than the general population4. There are no specific therapies available that protect individuals against AP-MODS. Here, we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism5, is central to the pathogenesis of AP-MODS. We created a mouse strain deficient for Kmo with a robust biochemical phenotype that protected against extrapancreatic tissue injury to lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Ă
resolution. Treatment with GSK180 resulted in rapid changes in levels of kynurenine pathway metabolites in vivo and afforded therapeutic protection against AP-MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS and open up a new area for drug discovery in critical illness
SynthÚse stéréosélective de pipéridines substituées (synthÚse de la (-)-paroxétine et approche de la (-)-velbanamine)
PARIS-BIUSJ-ThĂšses (751052125) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF
A Diverted Total Synthesis of Mycolactone Analogues: An Insight into Buruli Ulcer Toxins
International audienceMycolactones are complex macrolides responsible for a severe necrotizing skin disease called Buruli ulcer. Deciphering their functional interactions is of fundamental importance for the understanding, and ultimately, the control of this devastating mycobacterial infection. We report herein a diverted total synthesis approach of mycolactones analogues and provide the first insights into their structureâactivity relationship based on cytopathic assays on L929 fibroblasts. The lowest concentration inducing a cytopathic effect was determined for selected analogues, allowing a clear picture to emerge by comparison with the natural toxins
A new AMPK activator, GSK773, corrects fatty acid oxidation and differentiation defect in CPT2-deficient myotubes
International audienceCarnitine palmitoyl transferase 2 (CPT2) deficiency is one of the most common inherited fatty acid oxidation (FAO) defects and represents a prototypical mitochondrial metabolic myopathy. Recent studies have suggested a pivotal role of adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle plasticity and mitochondrial homeostasis. Thus, we tested the potential of GSK773, a novel direct AMPK activator, to improve or correct FAO capacities in muscle cells from patients harboring various mutations. We used controls' and patients' myotubes and studied the parameters of FAO metabolism, of mitochondrial quantity and quality and of differentiation. We found that AMPK is constitutively activated in patients' myotubes, which exhibit both reduced FAO and impaired differentiation. GSK773 improves or corrects several metabolic hallmarks of CPT2 deficiency (deficient FAO flux and C16-acylcarnitine accumulation) by upregulating the expression of CPT2 protein. Beneficial effects of GSK773 are also likely due to stimulation of mitochondrial biogenesis and induction of mitochondrial fusion, by decreasing dynamin-related protein 1 and increasing mitofusin 2. GSK773 also induces a shift in myosin heavy chain isoforms toward the slow oxidative type and, therefore, fully corrects the differentiation process. We establish, through small interfering RNA knockdowns and pharmacological approaches, that these GSK773 effects are mediated through peroxisome proliferator-activated receptor gamma co-activator 1-alpha, reactive oxygen species and p38 mitogen-activated protein kinase, all key players of skeletal muscle plasticity. GSK773 recapitulates several important features of skeletal muscle adaptation to exercise. The results show that AMPK activation by GSK773 evokes the slow, oxidative myogenic program and triggers beneficial phenotypic adaptations in FAO-deficient myotubes. Thus, GSK773 might have therapeutic potential for correction of CPT2 deficiency
Deep Generative Models for Ligand-based de Novo Design Applied to Multi-parametric Optimization
Multi-Parameter Optimization (MPO) is a major challenge in New Chemical Entity (NCE) drug discovery
projects, and the inability to identify molecules meeting all the criteria of lead optimization (LO) is an
important cause of NCE project failure. Several ligand- and structure-based de novo design methods
have been published over the past decades, some of which have proved useful multiobjective
optimization. However, there is still need for improvement to better address the chemical feasibility
of generated compounds as well as increasing the explored chemical space while tackling the MPO
challenge. Recently, promising results have been reported for deep learning generative models applied
to de novo molecular design, but until now, to our knowledge, no report has been made of the value
of this new technology for addressing MPO in an actual drug discovery project. Our objective in this
study was to evaluate the potential of a ligand-based de novo design technology using deep learning
generative models to accelerate the discovery of an optimized lead compound meeting all in vitro late
stage LO criteria.
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Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia
Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies1. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction2, 3. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC2, 3 and the polymerase-associated factor complex (PAFc)4, 5, are associated with the BET family of acetyl-lysine recognizing, chromatin âadaptorâ proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLLâAF9 and human MLLâAF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias
Discovery of Epigenetic Regulator IâBET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains
The
bromo and extra C-terminal domain (BET) family of bromodomains
are involved in binding epigenetic marks on histone proteins, more
specifically acetylated lysine residues. This paper describes the
discovery and structureâactivity relationships (SAR) of potent
benzodiazepine inhibitors that disrupt the function of the BET family
of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent,
selective compound I-BET762 that is now under evaluation in a phase
I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma
and other cancers
The Discovery of IâBET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor
Through
their function as epigenetic readers of the histone code,
the BET family of bromodomain-containing proteins regulate expression
of multiple genes of therapeutic relevance, including those involved
in tumor cell growth and inflammation. BET bromodomain inhibitors
have profound antiproliferative and anti-inflammatory effects which
translate into efficacy in oncology and inflammation models, and the
first compounds have now progressed into clinical trials. The exciting
biology of the BETs has led to great interest in the discovery of
novel inhibitor classes. Here we describe the identification of a
novel tetrahydroquinoline series through up-regulation of apolipoprotein
A1 and the optimization into potent compounds active in murine models
of septic shock and neuroblastoma. At the molecular level, these effects
are produced by inhibition of BET bromodomains. X-ray crystallography
reveals the interactions explaining the structureâactivity
relationships of binding. The resulting lead molecule, I-BET726, represents
a new, potent, and selective class of tetrahydroquinoline-based BET
inhibitors