RESUMEN
The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to the current standard of care. Therefore, MCL1 is an attractive anticancer target. Here we describe BRD-810 as a potent and selective MCL1 inhibitor and its key design principle of rapid systemic clearance to potentially minimize area under the curve-driven toxicities associated with MCL1 inhibition. BRD-810 induced rapid cell killing within 4 h in vitro but, in the same 4-h window, had no impact on cell viability or troponin I release in human induced pluripotent stem cell-derived cardiomyocytes, even at suprapharmacologic concentrations. In vivo BRD-810 induced efficacy in xenograft hematological and solid tumor models despite the short residence time of BRD-810 in plasma. In totality, our data support the hypothesis that short-term inhibition of MCL1 with BRD-810 can induce apoptosis in tumor cells while maintaining an acceptable safety profile. We, therefore, intend to advance BRD-810 to clinical trials.
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The difficulty in treating Gram-negative bacteria can largely be attributed to their highly impermeable outer membrane (OM), which serves as a barrier to many otherwise active antibiotics. This can be overcome with the use of perturbant molecules, which disrupt OM integrity and sensitize Gram-negative bacteria to many clinically available Gram-positive-active antibiotics. Although many new perturbants have been identified in recent years, most of these molecules are impeded by toxicity due to the similarities between pathogen and host cell membranes. For example, our group recently reported the cryptic OM-perturbing activity of the antiprotozoal drug pentamidine. Its development as an antibiotic adjuvant is limited, however, by toxicity concerns. Herein, we took a medicinal chemistry approach to develop novel analogs of pentamidine, aiming to improve its OM activity while reducing its off-target toxicity. We identified the compound P35, which induces OM disruption and potentiates Gram-positive-active antibiotics in Acinetobacter baumannii and Klebsiella pneumoniae. Relative to pentamidine, P35 has reduced mammalian cell cytotoxicity and hERG trafficking inhibition. Additionally, P35 outperforms pentamidine in a murine model of A. baumannii bacteremia. Together, this preclinical analysis supports P35 as a promising lead for further development as an OM perturbant.
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Acinetobacter baumannii , Antibacterianos , Acinetobacter baumannii/metabolismo , Animales , Antibacterianos/química , Bacterias Gramnegativas/metabolismo , Klebsiella pneumoniae/metabolismo , Mamíferos/metabolismo , Ratones , Pentamidina/metabolismo , Pentamidina/farmacologíaRESUMEN
OBJECTIVES: Racial and socioeconomic disparities in the incidence of Legionnaires' disease have been documented for the past 2 decades; however, the social determinants of health (SDH) that contribute to these disparities are not well studied. The objective of this narrative review was to characterize SDH to inform efforts to reduce disparities in the incidence of Legionnaires' disease. METHODS: We conducted a narrative review of articles published from January 1979 through October 2019 that focused on disparities in the incidence of Legionnaires' disease and pneumonia (inclusive of bacterial pneumonia and/or community-acquired pneumonia) among adults and children (excluding articles that were limited to people aged <18 years). We identified 220 articles, of which 19 met our criteria: original research, published in English, and examined Legionnaires' disease or pneumonia, health disparities, and SDH. We organized findings using the Healthy People 2030 SDH domains: economic stability, education access and quality, social and community context, health care access and quality, and neighborhood and built environment. RESULTS: Of the 19 articles reviewed, multiple articles examined disparities in incidence of Legionnaires' disease and pneumonia related to economic stability/income (n = 13) and comorbidities (n = 10), and fewer articles incorporated SDH variables related to education (n = 3), social support (none), health care access (n = 1), and neighborhood and built environment (n = 6) in their analyses. CONCLUSIONS: Neighborhood and built-environment factors such as housing, drinking water infrastructure, and pollutant exposures represent critical partnership and research opportunities. More research that incorporates SDH and multilevel, cross-sector interventions is needed to address disparities in Legionnaires' disease incidence.
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Infecciones Comunitarias Adquiridas , Enfermedad de los Legionarios , Neumonía , Adulto , Niño , Infecciones Comunitarias Adquiridas/epidemiología , Infecciones Comunitarias Adquiridas/microbiología , Humanos , Incidencia , Enfermedad de los Legionarios/epidemiología , Neumonía/epidemiología , Determinantes Sociales de la SaludRESUMEN
The outer membrane of Gram-negative bacteria is a formidable permeability barrier which allows only a small subset of chemical matter to penetrate. This outer membrane barrier can hinder the study of cellular processes and compound mechanism of action, as many compounds including antibiotics are precluded from entry despite having intracellular targets. Consequently, outer membrane permeabilizing compounds are invaluable tools in such studies. Many existing compounds known to perturb the outer membrane also impact inner membrane integrity, such as polymyxins and their derivatives, making these probes nonspecific. We performed a screen of â¼140â¯000 diverse synthetic compounds, for those that antagonized the growth inhibitory activity of vancomycin at 15 °C in Escherichia coli, to enrich for chemicals capable of perturbing the outer membrane. This led to the discovery that liproxstatin-1, an inhibitor of ferroptosis in human cells, and MAC-0568743, a novel cationic amphiphile, could potentiate the activity of large-scaffold antibiotics with low permeation into Gram-negative bacteria at 37 °C. Liproxstatin-1 and MAC-0568743 were found to physically disrupt the integrity of the outer membrane through interactions with lipopolysaccharide in the outer leaflet of the outer membrane. We showed that these compounds selectively disrupt the outer membrane while minimally impacting inner membrane integrity, particularly at the concentrations needed to potentiate Gram-positive-targeting antibiotics. Further exploration of these molecules and their structural analogues is a promising avenue for the development of outer membrane specific probes.
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Antibacterianos/química , Proteínas de la Membrana Bacteriana Externa/metabolismo , Pared Celular/efectos de los fármacos , Vancomicina/química , Acinetobacter baumannii/metabolismo , Antibacterianos/metabolismo , Antibacterianos/farmacología , Permeabilidad de la Membrana Celular , Pared Celular/metabolismo , Sinergismo Farmacológico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Escherichia coli/metabolismo , Escherichia coli/ultraestructura , Ensayos Analíticos de Alto Rendimiento , Klebsiella pneumoniae/metabolismo , Lipopolisacáridos/química , Lipopolisacáridos/metabolismo , Polimixinas/química , Polimixinas/metabolismo , Pseudomonas aeruginosa/metabolismo , Quinoxalinas/química , Quinoxalinas/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/metabolismo , Vancomicina/metabolismo , Vancomicina/farmacologíaRESUMEN
Atherosclerotic vascular disease resulting from unstable plaques is the leading cause of morbidity and mortality in subjects with type 2 diabetes (T2D), and thus a major therapeutic goal is to discover T2D drugs that can also promote atherosclerotic plaque stability. Genetic or pharmacologic inhibition of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2 or MK2) in obese mice improves glucose homeostasis and enhances insulin sensitivity. We developed two novel orally active small-molecule inhibitors of MK2, TBX-1 and TBX-2, and tested their effects on metabolism and atherosclerosis in high-fat Western diet (WD)-fed Ldlr-/- mice. Ldlr-/- mice were first fed the WD to allow atherosclerotic lesions to become established, and the mice were then treated with TBX-1 or TBX-2. Both compounds improved glucose metabolism and lowered plasma cholesterol and triglyceride, without an effect on body weight. Most importantly, the compounds decreased lesion area, lessened plaque necrosis, and increased fibrous cap thickness in the aortic root lesions of the mice. Thus, in a preclinical model of high-fat feeding and established atherosclerosis, MK2 inhibitors improved metabolism and also enhanced atherosclerotic plaque stability, suggesting potential for further clinical development to address the epidemic of T2D associated with atherosclerotic vascular disease.
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Aterosclerosis/enzimología , Aterosclerosis/patología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Placa Aterosclerótica/enzimología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Animales , Aorta/patología , Aterosclerosis/sangre , Glucosa/metabolismo , Homeostasis/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lípidos/sangre , Masculino , Ratones Endogámicos C57BL , Necrosis , Placa Aterosclerótica/sangre , Placa Aterosclerótica/patología , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
We piloted a methodology for collecting and interpreting root cause-or environmental deficiency (ED)-information from Legionnaires' disease (LD) outbreak investigation reports. The methodology included a classification framework to assess common failures observed in the implementation of water management programs (WMPs). We reviewed reports from fourteen CDC-led investigations between 1 January 2015 and 21 June 2019 to identify EDs associated with outbreaks of LD. We developed an abstraction guide to standardize data collection from outbreak reports and define relevant parameters. We categorized each ED according to three criteria: ED type, WMP-deficiency type, and source of deficiency. We calculated the prevalence of EDs among facilities and explored differences between facilities with and without WMPs. A majority of EDs identified (81%) were classified as process failures. Facilities with WMPs (n = 8) had lower prevalence of EDs attributed to plumbed devices (9.1%) and infrastructure design (0%) than facilities without WMPs (n = 6; 33.3% and 24.2%, respectively). About three quarters (72%) of LD cases and 81% of the fatalities in our sample originated at facilities without a WMP. This report highlights the importance of WMPs in preventing and mitigating outbreaks of LD. Building water system process management is a primary obstacle toward limiting the root causes of LD outbreaks. Greater emphasis on the documentation, verification, validation, and continuous program review steps will be important in maximizing the effectiveness of WMPs.
RESUMEN
Proprotein convertase substilisin-like/kexin type 9 (PCSK9) is a serine protease involved in a protein-protein interaction with the low-density lipoprotein (LDL) receptor that has both human genetic and clinical validation. Blocking this protein-protein interaction prevents LDL receptor degradation and thereby decreases LDL cholesterol levels. Our pursuit of small-molecule direct binders for this difficult to drug PPI target utilized affinity selection/mass spectrometry, which identified one confirmed hit compound. An X-ray crystal structure revealed that this compound was binding in an unprecedented allosteric pocket located between the catalytic and C-terminal domain. Optimization of this initial hit, using two distinct strategies, led to compounds with high binding affinity to PCSK9. Direct target engagement was demonstrated in the cell lysate with a cellular thermal shift assay. Finally, ligand-induced protein degradation was shown with a proteasome recruiting tag attached to the high-affinity allosteric ligand for PCSK9.
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Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Proproteína Convertasa 9/metabolismo , Proteolisis/efectos de los fármacos , Inhibidores de Serina Proteinasa/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Inhibidores de Serina Proteinasa/química , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
New antibiotics are needed to combat rising levels of resistance, with new Mycobacterium tuberculosis (Mtb) drugs having the highest priority. However, conventional whole-cell and biochemical antibiotic screens have failed. Here we develop a strategy termed PROSPECT (primary screening of strains to prioritize expanded chemistry and targets), in which we screen compounds against pools of strains depleted of essential bacterial targets. We engineered strains that target 474 essential Mtb genes and screened pools of 100-150 strains against activity-enriched and unbiased compound libraries, probing more than 8.5 million chemical-genetic interactions. Primary screens identified over tenfold more hits than screening wild-type Mtb alone, with chemical-genetic interactions providing immediate, direct target insights. We identified over 40 compounds that target DNA gyrase, the cell wall, tryptophan, folate biosynthesis and RNA polymerase, as well as inhibitors that target EfpA. Chemical optimization yielded EfpA inhibitors with potent wild-type activity, thus demonstrating the ability of PROSPECT to yield inhibitors against targets that would have eluded conventional drug discovery.
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Antituberculosos/clasificación , Antituberculosos/aislamiento & purificación , Descubrimiento de Drogas/métodos , Eliminación de Gen , Pruebas de Sensibilidad Microbiana/métodos , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Bibliotecas de Moléculas Pequeñas/farmacología , Antituberculosos/farmacología , Girasa de ADN/metabolismo , Farmacorresistencia Microbiana , Ácido Fólico/biosíntesis , Terapia Molecular Dirigida , Mycobacterium tuberculosis/citología , Mycobacterium tuberculosis/enzimología , Ácidos Micólicos/metabolismo , Reproducibilidad de los Resultados , Bibliotecas de Moléculas Pequeñas/clasificación , Bibliotecas de Moléculas Pequeñas/aislamiento & purificación , Especificidad por Sustrato , Inhibidores de Topoisomerasa II/aislamiento & purificación , Inhibidores de Topoisomerasa II/farmacología , Triptófano/biosíntesis , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiologíaRESUMEN
Previous work established a coumarin scaffold as a starting point for inhibition of Mycobacterium tuberculosis (Mtb) FadD32 enzymatic activity. After further profiling of the coumarin inhibitor 4 revealed chemical instability, we discovered that a quinoline ring circumvented this instability and had the advantage of offering additional substitution vectors to further optimize. Ensuing SAR studies gave rise to quinoline-2-carboxamides with potent anti-tubercular activity. Further optimization of ADME/PK properties culminated in 21b that exhibited compelling in vivo efficacy in a mouse model of Mtb infection.
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Antituberculosos/química , Proteínas Bacterianas/antagonistas & inhibidores , Cumarinas/química , Animales , Antituberculosos/metabolismo , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Proteínas Bacterianas/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ratones , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/metabolismo , Quinolinas/química , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiologíaRESUMEN
OBJECTIVE: Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by anacetrapib. APPROACH AND RESULTS: We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of anacetrapib on the metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo for 4 weeks, and then atorvastatin plus anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of anacetrapib treatment. We performed stable isotope kinetic studies using 2H3-leucine at the end of each treatment to measure apo(a) fractional catabolic rate and production rate. Median baseline Lp(a) levels were 21.5 nmol/L (interquartile range, 9.9-108.1 nmol/L) in the complete cohort (39 subjects) and 52.9 nmol/L (interquartile range, 38.4-121.3 nmol/L) in the subset selected for kinetic studies. Anacetrapib treatment lowered Lp(a) by 34.1% (P≤0.001) and 39.6% in the complete and subset cohort, respectively. The decreases in Lp(a) levels were because of a 41% reduction in the apo(a) production rate, with no effects on apo(a) fractional catabolic rate. CONCLUSIONS: Anacetrapib reduces Lp(a) levels by decreasing its production. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808.
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Anticolesterolemiantes/uso terapéutico , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Hipercolesterolemia/tratamiento farmacológico , Lipoproteína(a)/sangre , Oxazolidinonas/uso terapéutico , Adulto , Anciano , Anticolesterolemiantes/efectos adversos , Biomarcadores/sangre , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Cromatografía Liquida , Método Doble Ciego , Regulación hacia Abajo , Femenino , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/diagnóstico , Masculino , Persona de Mediana Edad , Ciudad de Nueva York , Oxazolidinonas/efectos adversos , Pennsylvania , Índice de Severidad de la Enfermedad , Espectrometría de Masas en Tándem , Factores de Tiempo , Resultado del TratamientoRESUMEN
Modification of a gut restricted class of benzimidazole DGAT1 inhibitor 1 led to 9 with good oral bioavailability. The key structural changes to 1 include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both 1 and 9 can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only 9 was found to be effective in suppressing body weight gain relative to control in a diet-induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body weight control. 9 has advanced to clinical investigation and successfully suppressed postprandial triglycerides during an acute meal challenge in humans.
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Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Dieta Alta en Grasa , Inhibidores Enzimáticos/farmacología , Obesidad/fisiopatología , Triglicéridos/sangre , Aumento de Peso/efectos de los fármacos , Administración Oral , Adolescente , Adulto , Animales , Perros , Método Doble Ciego , Descubrimiento de Drogas , Inhibidores Enzimáticos/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placebos , Periodo Posprandial , Ratas , Ratas Sprague-Dawley , Adulto JovenRESUMEN
OBJECTIVES To define the scope of an outbreak of Legionnaires' disease (LD), to identify the source, and to stop transmission. DESIGN AND SETTING Epidemiologic investigation of an LD outbreak among patients and a visitor exposed to a newly constructed hematology-oncology unit. METHODS An LD case was defined as radiographically confirmed pneumonia in a person with positive urinary antigen testing and/or respiratory culture for Legionella and exposure to the hematology-oncology unit after February 20, 2014. Cases were classified as definitely or probably healthcare-associated based on whether they were exposed to the unit for all or part of the incubation period (2-10 days). We conducted an environmental assessment and collected water samples for culture. Clinical and environmental isolates were compared by monoclonal antibody (MAb) and sequence-based typing. RESULTS Over a 12-week period, 10 cases were identified, including 6 definite and 4 probable cases. Environmental sampling revealed Legionella pneumophila serogroup 1 (Lp1) in the potable water at 9 of 10 unit sites (90%), including all patient rooms tested. The 3 clinical isolates were identical to environmental isolates from the unit (MAb2-positive, sequence type ST36). No cases occurred with exposure after the implementation of water restrictions followed by point-of-use filters. CONCLUSIONS Contamination of the unit's potable water system with Lp1 strain ST36 was the likely source of this outbreak. Healthcare providers should routinely test patients who develop pneumonia at least 2 days after hospital admission for LD. A single case of LD that is definitely healthcare associated should prompt a full investigation. Infect Control Hosp Epidemiol 2017;38:306-313.
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Infección Hospitalaria/etiología , Brotes de Enfermedades , Agua Potable/microbiología , Enfermedad de los Legionarios/diagnóstico , Enfermedad de los Legionarios/transmisión , Adulto , Anciano , Anciano de 80 o más Años , Alabama , Infección Hospitalaria/microbiología , Femenino , Hematología , Humanos , Legionella pneumophila/clasificación , Legionella pneumophila/aislamiento & purificación , Masculino , Persona de Mediana Edad , Servicio de Oncología en Hospital , Microbiología del AguaRESUMEN
Circulating low-density lipoprotein cholesterol (LDLc) is regulated by membrane-bound LDL receptor (LDLr). Upon LDLc and LDLr interaction the complex is internalized by the cell, leading to LDLc degradation and LDLr recycling back to the cell surface. The proprotein convertase subtilisin/kexin type 9 (PCSK9) protein regulates this cycling. PCSK9 is secreted from the cell and binds LDLr. When the complex is internalized, PCSK9 prevents LDLr from shuttling back to the surface and instead targets it for degradation. PCSK9 is a serine protease expressed as a zymogen that undergoes autoproteolysis, though the two resulting protein domains remain stably associated as a heterodimer. This PCSK9 autoprocessing is required for the protein to be secreted from the cell. To date, direct analysis of PCSK9 autoprocessing has proven challenging, as no catalytically active zymogen has been isolated. A PCSK9 loss-of-function point mutation (Q152H) that reduces LDLc levels two-fold was identified in a patient population. LDLc reduction was attributed to a lack of PCSK9(Q152H) autoprocessing preventing secretion of the protein. We have isolated a zymogen form of PCSK9, PCSK9(Q152H), and a related mutation (Q152N), that can undergo slow autoproteolysis. We show that the point mutation prevents the formation of the mature form of PCSK9 by hindering folding, reducing the rate of autoproteolysis, and destabilizing the heterodimeric form of the protein. In addition, we show that the zymogen form of PCSK9 adopts a structure that is distinct from the processed form and is unable to bind a mimetic peptide based on the EGF-A domain of the LDLr.
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Péptidos/química , Mutación Puntual , Proproteína Convertasa 9/química , Multimerización de Proteína , Receptores de LDL/química , Sustitución de Aminoácidos , Humanos , Péptidos/genética , Péptidos/metabolismo , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , Unión Proteica , Dominios Proteicos , Receptores de LDL/genética , Receptores de LDL/metabolismoRESUMEN
DGAT2 plays a critical role in hepatic triglyceride production, and data suggests that inhibition of DGAT2 could prove to be beneficial in treating a number of disease states. This article documents the discovery and optimization of a selective small molecule inhibitor of DGAT2 as well as pharmacological proof of biology in a mouse model of triglyceride production.
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Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Isoquinolinas/química , Isoquinolinas/farmacología , Triglicéridos/metabolismo , Animales , Diacilglicerol O-Acetiltransferasa/metabolismo , Descubrimiento de Drogas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Humanos , Isoquinolinas/administración & dosificación , Isoquinolinas/farmacocinética , Masculino , Ratones , Ratones Endogámicos C57BL , Triglicéridos/sangreRESUMEN
Stable isotope tracers are widely used to quantify metabolic rates, and yet a limited number of studies have considered the impact of analytical error on estimates of flux. For example, when estimating the contribution of de novo lipogenesis, one typically measures a minimum of four isotope ratios, i.e., the precursor and product labeling pre- and posttracer administration. This seemingly simple problem has 1 correct solution and 80 erroneous outcomes. In this report, we outline a methodology for evaluating the effect of error propagation on apparent physiological endpoints. We demonstrate examples of how to evaluate the influence of analytical error in case studies concerning lipid and protein synthesis; we have focused on (2)H2O as a tracer and contrast different mass spectrometry platforms including GC-quadrupole-MS, GC-pyrolysis-IRMS, LC-quadrupole-MS, and high-resolution FT-ICR-MS. The method outlined herein can be used to determine how to minimize variations in the apparent biology by altering the dose and/or the type of tracer. Likewise, one can facilitate biological studies by estimating the reduction in the noise of an outcome that is expected for a given increase in the number of replicate injections.
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Marcaje Isotópico/métodos , Espectrometría de Masas/métodos , Metabolismo , Animales , Isótopos de Carbono , Cromatografía de Gases/métodos , Cromatografía Liquida/métodos , Óxido de Deuterio , Humanos , Relación Señal-RuidoRESUMEN
The prevalence of obesity-induced type 2 diabetes (T2D) is increasing worldwide, and new treatment strategies are needed. We recently discovered that obesity activates a previously unknown pathway that promotes both excessive hepatic glucose production (HGP) and defective insulin signaling in hepatocytes, leading to exacerbation of hyperglycemia and insulin resistance in obesity. At the hub of this new pathway is a kinase cascade involving calcium/calmodulin-dependent protein kinase II (CaMKII), p38α mitogen-activated protein kinase (MAPK), and MAPKAPK2/3 (MK2/3). Genetic-based inhibition of these kinases improves metabolism in obese mice. Here, we report that treatment of obese insulin-resistant mice with an allosteric MK2/3 inhibitor, compound (cmpd) 28, ameliorates glucose homeostasis by suppressing excessive HGP and enhancing insulin signaling. The metabolic improvement seen with cmpd 28 is additive with the leading T2D drug, metformin, but it is not additive with dominant-negative MK2, suggesting an on-target mechanism of action. Allosteric MK2/3 inhibitors represent a potentially new approach to T2D that is highly mechanism based, has links to human T2D, and is predicted to avoid certain adverse effects seen with current T2D drugs.