Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD(+), essential for cellular metabolism, energy production, and DNA repair. NAMPT ...has been extensively studied because of its critical role in these cellular processes and the prospect of developing therapeutics against the target, yet how it regulates cellular metabolism is not fully understood. In this study we utilized liquid chromatography-mass spectrometry to examine the effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, and serine biosynthesis in cancer cells and tumor xenografts. We show for the first time that NAMPT inhibition leads to the attenuation of glycolysis at the glyceraldehyde 3-phosphate dehydrogenase step due to the reduced availability of NAD(+) for the enzyme. The attenuation of glycolysis results in the accumulation of glycolytic intermediates before and at the glyceraldehyde 3-phosphate dehydrogenase step, promoting carbon overflow into the pentose phosphate pathway as evidenced by the increased intermediate levels. The attenuation of glycolysis also causes decreased glycolytic intermediates after the glyceraldehyde 3-phosphate dehydrogenase step, thereby reducing carbon flow into serine biosynthesis and the TCA cycle. Labeling studies establish that the carbon overflow into the pentose phosphate pathway is mainly through its non-oxidative branch. Together, these studies establish the blockade of glycolysis at the glyceraldehyde 3-phosphate dehydrogenase step as the central metabolic basis of NAMPT inhibition responsible for ATP depletion, metabolic perturbation, and subsequent tumor growth inhibition. These studies also suggest that altered metabolite levels in tumors can be used as robust pharmacodynamic markers for evaluating NAMPT inhibitors in the clinic.
NAMPT, an enzyme essential for NAD
biosynthesis, has been extensively studied as an anticancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some ...of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective and has a potent and broad spectrum of anticancer activity. Its inhibitory activity can be rescued with nicotinic acid (NA) against the cell lines proficient, but not those deficient in NAPRT1, essential for converting NA to NAD
LSN3154567 also exhibits robust efficacy in multiple tumor models deficient in NAPRT1. Importantly, this molecule when coadministered with NA does not cause observable retinal and hematological toxicities in the rodents, yet still retains robust efficacy. Thus, LSN3154567 has the potential to be further developed clinically into a novel cancer therapeutic.
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The route selection and process research and development of a practical synthesis for JAK2 inhibitor LY2784544 is described. The first-generation synthesis route, similar to that used in discovery ...for derivatization of a benzylic amine moiety, was 14 overall steps and possessed several steps that required extensive development for large-scale production. Route selection considerations led to a modified synthesis that utilized a novel vanadium-catalyzed carbon–carbon bond-forming arylation reaction for incorporation of the key benzylic morpholine moiety. A protecting group used to mask an amino pyrazole unit was modified from PMB to tert-butyl, resulting in a dramatic reduction in the overall length of the route. These two major changes resulted in an eight-step synthesis, which was six steps shorter than the first-generation synthesis. In the pilot plant, the new synthesis was scaled to produce >100 kg of LY2784544 in high yield and purity under GMP conditions. The overall development including the vanadium-catalyzed C–C bond-forming methodology, a ketone reductive deoxygenation, and a palladium-catalyzed amination is described.
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•Chiral DHP as hinge binder provided high AKT1 selectivity over ROCK2/AGC kinases.•Emphasis on physicochemical properties over potency led to developable compounds.•Reducing the HB ...acceptor strength of compounds with high P-gp efflux improved Ppass.
During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3β in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model.
Stigma surrounding opioid use disorder (OUD) is a barrier to treatment. The use of stigmatizing language may be evidence of negative views toward patients.
We aimed to identify associations between ...language and clinical outcomes in patients admitted for infectious complications of OUD.
We performed a retrospective medical record review.
Four U.S. academic health systems. Participants were patients with OUD admitted for infectious complications of injection opioid use from January 1, 2018, to December 31, 2018, identified through international classification of diseases, 10th revision codes consistent with OUD and acute bacterial/fungal infection.
Discharge summaries were reviewed for language, specifically: abuse, addiction, dependence, misuse, use disorder, intravenous drug use, and others. Binary outcomes including medication for OUD, planned discharge, naloxone provision, and an OUD treatment plan were evaluated using logistic regressions and admission duration was evaluated using Gamma regression.
A total of 1285 records were reviewed and 328 met inclusion criteria. Of those, 191 (58%) were male, with a median age of 38 years. The most common term was "abuse" (219, 67%), whereas "use disorder" was recorded in 75 (23%) records. Having "use disorder" in the discharge summary was associated with increased odds of having a documented plan for ongoing OUD treatment (adjusted odds ratio AOR: 4.11, 95% confidence interval CI: 1.89-8.93) and having a documented plan for addiction-specific follow-up care (AOR: 2.31, 95% CI: 1.30-4.09).
Stigmatizing language was common in this study of patients hospitalized for infectious complications of OUD. Best-practice language was uncommon, but when used was associated with increased odds of addiction treatment and specialty care referrals.
Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an ...attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7 − 12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.
Tumor angiogenesis is a highly regulated process involving intercellular communication as well as the interactions of multiple downstream signal transduction pathways. Disrupting one or even a few ...angiogenesis pathways is often insufficient to achieve sustained therapeutic benefits due to the complexity of angiogenesis. Targeting multiple angiogenic pathways has been increasingly recognized as a viable strategy. However, translation of the polypharmacology of a given compound to its antiangiogenic efficacy remains a major technical challenge. Developing a global functional association network among angiogenesis-related genes is much needed to facilitate holistic understanding of angiogenesis and to aid the development of more effective anti-angiogenesis therapeutics.
We constructed a comprehensive gene functional association network or interactome by transcript profiling an in vitro angiogenesis model, in which human umbilical vein endothelial cells (HUVECs) formed capillary structures when co-cultured with normal human dermal fibroblasts (NHDFs). HUVEC competence and NHDF supportiveness of cord formation were found to be highly cell-passage dependent. An enrichment test of Biological Processes (BP) of differentially expressed genes (DEG) revealed that angiogenesis related BP categories significantly changed with cell passages. Built upon 2012 DEGs identified from two microarray studies, the resulting interactome captured 17226 functional gene associations and displayed characteristics of a scale-free network. The interactome includes the involvement of oncogenes and tumor suppressor genes in angiogenesis. We developed a network walking algorithm to extract connectivity information from the interactome and applied it to simulate the level of network perturbation by three multi-targeted anti-angiogenic kinase inhibitors. Simulated network perturbation correlated with observed anti-angiogenesis activity in a cord formation bioassay.
We established a comprehensive gene functional association network to model in vitro angiogenesis regulation. The present study provided a proof-of-concept pilot of applying network perturbation analysis to drug phenotypic activity assessment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The design, synthesis, and structure activity relationships for a novel series of indoles as potent, selective, thyroid hormone receptor β (TRβ) agonists is described. Compounds with >50× binding ...selectivity for TRβ over TRα were generated and evaluation of compound 1c from this series in a model of dyslipidemia demonstrated positive effects on plasma lipid endpoints in vivo. Display omitted
The design, synthesis, and structure activity relationships for a novel series of indoles as potent, selective, thyroid hormone receptor β (TRβ) agonists is described. Compounds with >50× binding selectivity for TRβ over TRα were generated and evaluation of compound 1c from this series in a model of dyslipidemia demonstrated positive effects on plasma lipid endpoints in vivo.
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD+, essential for cellular metabolism, energy production, and DNA repair. NAMPT ...has been extensively studied because of its critical role in these cellular processes and the prospect of developing therapeutics against the target, yet how it regulates cellular metabolism is not fully understood. In this study we utilized liquid chromatography-mass spectrometry to examine the effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, and serine biosynthesis in cancer cells and tumor xenografts. We show for the first time that NAMPT inhibition leads to the attenuation of glycolysis at the glyceraldehyde 3-phosphate dehydrogenase step due to the reduced availability of NAD+ for the enzyme. The attenuation of glycolysis results in the accumulation of glycolytic intermediates before and at the glyceraldehyde 3-phosphate dehydrogenase step, promoting carbon overflow into the pentose phosphate pathway as evidenced by the increased intermediate levels. The attenuation of glycolysis also causes decreased glycolytic intermediates after the glyceraldehyde 3-phosphate dehydrogenase step, thereby reducing carbon flow into serine biosynthesis and the TCA cycle. Labeling studies establish that the carbon overflow into the pentose phosphate pathway is mainly through its non-oxidative branch. Together, these studies establish the blockade of glycolysis at the glyceraldehyde 3-phosphate dehydrogenase step as the central metabolic basis of NAMPT inhibition responsible for ATP depletion, metabolic perturbation, and subsequent tumor growth inhibition. These studies also suggest that altered metabolite levels in tumors can be used as robust pharmacodynamic markers for evaluating NAMPT inhibitors in the clinic.
Background: NAMPT catalyzes the rate-limiting reaction in converting nicotinamide to NAD+ in cancers.
Results: NAMPT inhibition attenuates glycolysis at the glyceraldehyde 3-phosphate dehydrogenase step, resulting in perturbing metabolic pathways related to glycolysis.
Conclusion: The metabolic basis of NAMPT inhibition is the attenuation of glycolysis by reducing NAD+ available to glyceraldehyde 3-phosphate dehydrogenase.
Significance: This study sheds new light on how NAMPT regulates cancer metabolism.
3-(Imidazo1,2-
apyridin-3-yl)-, its aza-analogs, and 3-(pyrazolo1,5-
apyridin-3-yl)-4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl))maleimides are very potent inhibitors of GSK3 (⩽5
nM) ...with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII.
Many 3-aryl-4-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100
nM IC
50), although few show significant selectivity (>100
×) versus CDK2, CDK4, or PKCβII. However, combining 3-(imidazo1,2-
apyridin-3-yl), 3-(pyrazolo1,5-
apyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (⩽5
nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).
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