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1.
Nat Chem Biol ; 15(11): 1129, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31439938

RESUMEN

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

2.
Nat Chem Biol ; 15(8): 764-775, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31320759

RESUMEN

Accumulation of unfolded proteins at the endoplasmic reticulum (ER) is a salient attribute of many human diseases including obesity, liver disorders, cancer, diabetes and neurodegeneration. To restore ER proteostasis, cells activate the unfolded protein response (UPR), a signaling pathway that imposes adaptive programs or triggers apoptosis of damaged cells. The UPR is critical to sustain the normal function of specialized secretory cells (i.e., pancreatic ß cells and B lymphocytes) and to control the production of lipids and cholesterol in the liver. In the context of disease, adaptive UPR responses have been linked to the growth of solid tumors, whereas chronic ER stress contributes to cell dysfunction in brain diseases, metabolic syndromes, among other conditions. Here we discuss recent developments in the design and optimization of novel compounds to manipulate UPR signaling and their efficacy in various disease models.


Asunto(s)
Sistemas de Liberación de Medicamentos , Transducción de Señal , Respuesta de Proteína Desplegada , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/fisiología , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo
3.
Int J Mol Sci ; 22(3)2021 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-33530349

RESUMEN

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer's disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562.


Asunto(s)
Neuronas/efectos de los fármacos , Neuronas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Tauopatías/etiología , Tauopatías/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Ratones , Ratones Transgénicos , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Fosforilación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteoma , Proteómica/métodos , Índice de Severidad de la Enfermedad , Tauopatías/diagnóstico , Tauopatías/tratamiento farmacológico , Respuesta de Proteína Desplegada , eIF-2 Quinasa/metabolismo , Proteínas tau/metabolismo
4.
Hum Mol Genet ; 27(14): 2477-2489, 2018 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-29718201

RESUMEN

Marinesco-Sjögren syndrome (MSS) is a rare, early onset, autosomal recessive multisystem disorder characterized by cerebellar ataxia, cataracts and myopathy. Most MSS cases are caused by loss-of-function mutations in the gene encoding SIL1, a nucleotide exchange factor for the molecular chaperone BiP which is essential for correct protein folding in the endoplasmic reticulum. Woozy mice carrying a spontaneous Sil1 mutation recapitulate key pathological features of MSS, including cerebellar atrophy with degeneration of Purkinje cells and progressive myopathy. Because the PERK branch of the unfolded protein response is activated in degenerating neurons of woozy mice, and inhibiting PERK-mediated translational attenuation has shown protective effects in protein-misfolding neurodegenerative disease models, we tested the therapeutic efficacy of GSK2606414, a potent inhibitor of PERK. Mice were chronically treated with GSK2606414 starting from a presymptomatic stage, and the effects were evaluated on biochemical, histopathological and clinical readouts. GSK2606414 delayed Purkinje cell degeneration and the onset of motor deficits, prolonging the asymptomatic phase of the disease; it also reduced the skeletal muscle abnormalities and improved motor performance during the symptomatic phase. The protein but not the mRNA level of ORP150, a nucleotide exchange factor which can substitute for SIL1, was increased in the cerebellum of GSK2606414-treated woozy mice, suggesting that translational recovery promoted the synthesis of this alternative BiP co-factor. Targeting PERK signaling may have beneficial disease-modifying effects in carriers of SIL1 mutations.


Asunto(s)
Factores de Intercambio de Guanina Nucleótido/genética , Proteínas HSP70 de Choque Térmico/genética , Degeneración Nerviosa/genética , Degeneraciones Espinocerebelosas/terapia , eIF-2 Quinasa/genética , Adenina/administración & dosificación , Adenina/análogos & derivados , Animales , Cerebelo/efectos de los fármacos , Cerebelo/fisiopatología , Modelos Animales de Enfermedad , Retículo Endoplásmico/genética , Retículo Endoplásmico/patología , Heterocigoto , Humanos , Indoles/administración & dosificación , Mutación con Pérdida de Función/genética , Ratones , Actividad Motora/fisiología , Degeneración Nerviosa/fisiopatología , Pliegue de Proteína , Células de Purkinje/efectos de los fármacos , Células de Purkinje/patología , Degeneraciones Espinocerebelosas/genética , Degeneraciones Espinocerebelosas/patología , Respuesta de Proteína Desplegada/genética
5.
Neurobiol Dis ; 112: 136-148, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29355603

RESUMEN

Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to the progressive decline of motor control due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Accumulating evidence suggest that altered proteostasis is a salient feature of PD, highlighting perturbations to the endoplasmic reticulum (ER), the main compartment involved in protein folding and secretion. PERK is a central ER stress sensor that enforces adaptive programs to recover homeostasis through a block of protein translation and the induction of the transcription factor ATF4. In addition, chronic PERK signaling results in apoptosis induction and neuronal dysfunction due to the repression in the translation of synaptic proteins. Here we confirmed the activation of PERK signaling in postmortem brain tissue derived from PD patients and three different rodent models of the disease. Pharmacological targeting of PERK by the oral administration of GSK2606414 demonstrated efficient inhibition of the pathway in the SNpc after experimental ER stress stimulation. GSK2606414 protected nigral-dopaminergic neurons against a PD-inducing neurotoxin, improving motor performance. The neuroprotective effects of PERK inhibition were accompanied by an increase in dopamine levels and the expression of synaptic proteins. However, GSK2606414 treated animals developed secondary effects possibly related to pancreatic toxicity. This study suggests that strategies to attenuate ER stress levels may be effective to reduce neurodegeneration in PD.


Asunto(s)
Adenina/análogos & derivados , Modelos Animales de Enfermedad , Indoles/uso terapéutico , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/prevención & control , Transducción de Señal/efectos de los fármacos , eIF-2 Quinasa/antagonistas & inhibidores , Adenina/farmacología , Adenina/uso terapéutico , Animales , Femenino , Humanos , Indoles/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades Neurodegenerativas/inducido químicamente , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/prevención & control , Oxidopamina/toxicidad , Trastornos Parkinsonianos/inducido químicamente , Ratas , Ratas Sprague-Dawley , Transducción de Señal/fisiología , eIF-2 Quinasa/metabolismo
6.
Bioorg Med Chem Lett ; 22(12): 4028-32, 2012 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-22579486
7.
Biochem J ; 433(2): 357-69, 2011 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-21087210

RESUMEN

PDK1 (3-phosphoinositide-dependent protein kinase 1) activates a group of protein kinases belonging to the AGC [PKA (protein kinase A)/PKG (protein kinase G)/PKC (protein kinase C)]-kinase family that play important roles in mediating diverse biological processes. Many cancer-driving mutations induce activation of PDK1 targets including Akt, S6K (p70 ribosomal S6 kinase) and SGK (serum- and glucocorticoid-induced protein kinase). In the present paper, we describe the small molecule GSK2334470, which inhibits PDK1 with an IC50 of ~10 nM, but does not suppress the activity of 93 other protein kinases including 13 AGC-kinases most related to PDK1 at 500-fold higher concentrations. Addition of GSK2334470 to HEK (human embryonic kidney)-293, U87 or MEF (mouse embryonic fibroblast) cells ablated T-loop residue phosphorylation and activation of SGK isoforms and S6K1 induced by serum or IGF1 (insulin-like growth factor 1). GSK2334470 also inhibited T-loop phosphorylation and activation of Akt, but was more efficient at inhibiting Akt in response to stimuli such as serum that activated the PI3K (phosphoinositide 3-kinase) pathway weakly. GSK2334470 inhibited activation of an Akt1 mutant lacking the PH domain (pleckstrin homology domain) more potently than full-length Akt1, suggesting that GSK2334470 is more effective at inhibiting PDK1 substrates that are activated in the cytosol rather than at the plasma membrane. Consistent with this, GSK2334470 inhibited Akt activation in knock-in embryonic stem cells expressing a mutant of PDK1 that is unable to interact with phosphoinositides more potently than in wild-type cells. GSK2334470 also suppressed T-loop phosphorylation and activation of RSK2 (p90 ribosomal S6 kinase 2), another PDK1 target activated by the ERK (extracellular-signal-regulated kinase) pathway. However, prolonged treatment of cells with inhibitor was required to observe inhibition of RSK2, indicating that PDK1 substrates possess distinct T-loop dephosphorylation kinetics. Our data define how PDK1 inhibitors affect AGC signalling pathways and suggest that GSK2334470 will be a useful tool for delineating the roles of PDK1 in biological processes.


Asunto(s)
Indazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Animales , Células Cultivadas , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Humanos , Indazoles/química , Ratones , Estructura Molecular , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Pirimidinas/química , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal/efectos de los fármacos , Especificidad por Sustrato
8.
Cell Chem Biol ; 29(6): 947-957.e8, 2022 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-35202587

RESUMEN

In cystic fibrosis (CF), excessive furin activity plays a critical role in the activation of the epithelial sodium channel (ENaC), dysregulation of which contributes to airway dehydration, ineffective mucociliary clearance (MCC), and mucus obstruction. Here, we report a highly selective, cell-permeable furin inhibitor, BOS-318, that derives selectivity by eliciting the formation of a new, unexpected binding pocket independent of the active site catalytic triad. Using human ex vivo models, BOS-318 showed significant suppression of ENaC, which led to enhanced airway hydration and an ∼30-fold increase in MCC rate. Furin inhibition also protected ENaC from subsequent activation by neutrophil elastase, a soluble protease dominant in CF airways. Additional therapeutic benefits include protection against epithelial cell death induced by Pseudomonas aeruginosa exotoxin A. Our findings demonstrate the utility of selective furin inhibition as a mutation-agnostic approach that can correct features of CF airway pathophysiology in a manner expected to deliver therapeutic value.


Asunto(s)
Fibrosis Quística , Furina , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Canales Epiteliales de Sodio/genética , Canales Epiteliales de Sodio/metabolismo , Furina/antagonistas & inhibidores , Humanos , Depuración Mucociliar
9.
Bioorg Med Chem Lett ; 21(24): 7489-95, 2011 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-22047689
10.
Bioorg Med Chem Lett ; 20(8): 2552-5, 2010 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-20335034

RESUMEN

Novel Aurora inhibitors were identified truncating clinical candidate GSK1070916. Many of these truncated compounds retained potent activity against Aurora B with good antiproliferative activity. Mechanistic studies suggested that these compounds, depending on the substitution pattern, may or may not exert their antiproliferative effects via inhibition of Aurora B. The SAR results from this investigation will be presented with an emphasis on the impact structural changes have on the cellular phenotype.


Asunto(s)
Compuestos Aza/química , Indoles/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Aurora Quinasa B , Aurora Quinasas , Línea Celular Tumoral , Descubrimiento de Drogas , Citometría de Flujo , Humanos , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad
11.
Expert Opin Ther Pat ; 27(1): 37-48, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27646439

RESUMEN

INTRODUCTION: PKR-like endoplasmic reticulum kinase (PERK) is an essential component of the unfolded protein response (UPR) and a critical regulator of protein synthesis during endoplasmic reticulum (ER) stress. Transient PERK activation is protective; however, chronic ER stress and sustained PERK activation can be detrimental to cell health. Many diseases are associated with PERK over-activation, suggestive that small molecule PERK inhibitors may provide new opportunities for treating cancer and neurodegenerative diseases, among others. Areas covered: This review covers the therapeutic potential of PERK modulation and will focus more specifically on small molecule inhibitors of PERK disclosed in the patent literature from 2010-2015. During this time period the first PERK inhibitor patents appeared disclosing novel, potent, and selective inhibitors of PERK. Expert opinion: Compelling preclinical and clinical evidence supports the potential use of PERK modulators for a variety of diseases, particularly cancer and neurodegenerative disease. Potent and selective PERK inhibitors have been characterized pharmacologically and are available for further study. Despite high therapeutic potential, the future clinical use of PERK inhibitors will require thorough safety and toxicity evaluation to gauge therapeutic index and develop a framework for risk-benefit assessment.


Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , eIF-2 Quinasa/antagonistas & inhibidores , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/fisiopatología , Patentes como Asunto , Inhibidores de Proteínas Quinasas/efectos adversos , Respuesta de Proteína Desplegada/efectos de los fármacos
12.
Blood Adv ; 1(26): 2553-2562, 2017 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-29296907

RESUMEN

Neutropenia is a common consequence of radiation and chemotherapy in cancer patients. The resulting immunocompromised patients become highly susceptible to potentially life-threatening infections. Granulocyte colony-stimulating factor (G-CSF) is known to stimulate neutrophil production and is widely used as a treatment of chemotherapy-induced neutropenia. A small-molecule G-CSF secretagogue without a requirement for refrigerated supply chain would offer a more convenient and cost-effective treatment of chemotherapy-induced neutropenia. Bacterial lipopeptides activate innate immune responses through Toll-like receptor 2 (TLR2) and induce the release of cytokines, including G-CSF, from macrophages, monocytes, and endothelial. Pam2CSK4 is a synthetic lipopeptide that effectively mimics bacterial lipoproteins known to activate TLR2 receptor signaling through the TLR2/6 heterodimer. Substrate-based drug design led to the discovery of GSK3277329, which stimulated the release of G-CSF in activated THP-1 cells, peripheral blood mononuclear cells, and human umbilical vein endothelial cells. When administered subcutaneously to cynomolgus monkeys (Macaca fascicularis), GSK3277329 caused systemic elevation of G-CSF and interleukin-6 (IL-6), but not IL-1ß or tumor necrosis factor α, indicating a selective cytokine-stimulation profile. Repeat daily injections of GSK3277329 in healthy monkeys also raised circulating neutrophils above the normal range over a 1-week treatment period. More importantly, repeated daily injections of GSK3277329 over a 2-week period restored neutrophil loss in monkeys given chemotherapy treatment (cyclophosphamide, Cytoxan). These data demonstrate preclinical in vivo proof of concept that TLR2 agonism can drive both G-CSF induction and subsequent neutrophil elevation in the cynomolgus monkey and could be a therapeutic strategy for the treatment of chemotherapy-induced neutropenia.

13.
Cancer Chemother Pharmacol ; 72(1): 251-62, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23700291

RESUMEN

BACKGROUND: Inhibition of glucose metabolism has recently become an attractive target for cancer treatment. Accordingly, since 2-deoxyglucose (2-DG) competes effectively with glucose, it has come under increasing scrutiny as a therapeutic agent. The initial response of tumor cells to 2-DG is growth inhibition, which is thought to conserve energy and consequently protect cells from its ATP-lowering effects as a glycolytic inhibitor. However, since 2-DG also mimics mannose and thereby interferes with N-linked glycosylation, the question is raised of how this sugar analog inhibits tumor cell growth and whether the mechanism by which it protects cells can be manipulated to convert 2-DG-induced growth inhibition to cell death. METHODS: Cell growth and death were measured via counting viable and dead cells based on trypan blue exclusion. Markers of ATP reduction and the unfolded protein response (UPR) were detected by Western blot. Protein functions were manipulated through chemical compounds, siRNA and the use of gene-specific wild-type and knock-out mouse embryonic fibroblasts (MEFs). RESULTS: At 2-DG concentrations that can be achieved in human plasma without causing significant side effects, we find (a) It induces growth inhibition predominantly by interference with glycosylation, which leads to accumulation of unfolded proteins in the endoplasmic reticulum activating the UPR; (b) Inhibition of PERK (but not ATF6 or IRE1), a major component of the UPR, leads to conversion of 2-DG-induced growth inhibition to cell death and (c) secondarily to PERK, inhibition of GCN2, a kinase that is activated in response to low intracellular glutamine, increases 2-DG's cytotoxic effects in PERK -/- MEFs. CONCLUSIONS: Overall, these findings present a novel anticancer strategy that can be translated into therapeutic gain as they uncover the metabolic target PERK, and to a lesser degree GCN2, that when inhibited convert 2-DG's static effect to a toxic one in tumor cells growing under normoxia.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Desoxiglucosa/farmacología , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Respuesta de Proteína Desplegada/efectos de los fármacos , eIF-2 Quinasa/antagonistas & inhibidores , Factor de Transcripción Activador 6/antagonistas & inhibidores , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/metabolismo , Animales , Biomarcadores/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Glicosilación/efectos de los fármacos , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Neoplasias/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismo
14.
Sci Transl Med ; 5(206): 206ra138, 2013 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-24107777

RESUMEN

During prion disease, an increase in misfolded prion protein (PrP) generated by prion replication leads to sustained overactivation of the branch of the unfolded protein response (UPR) that controls the initiation of protein synthesis. This results in persistent repression of translation, resulting in the loss of critical proteins that leads to synaptic failure and neuronal death. We have previously reported that localized genetic manipulation of this pathway rescues shutdown of translation and prevents neurodegeneration in a mouse model of prion disease, suggesting that pharmacological inhibition of this pathway might be of therapeutic benefit. We show that oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA-like endoplasmic reticulum kinase), a key mediator of this UPR pathway, prevented UPR-mediated translational repression and abrogated development of clinical prion disease in mice, with neuroprotection observed throughout the mouse brain. This was the case for animals treated both at the preclinical stage and also later in disease when behavioral signs had emerged. Critically, the compound acts downstream and independently of the primary pathogenic process of prion replication and is effective despite continuing accumulation of misfolded PrP. These data suggest that PERK, and other members of this pathway, may be new therapeutic targets for developing drugs against prion disease or other neurodegenerative diseases where the UPR has been implicated.


Asunto(s)
Adenina/análogos & derivados , Indoles/administración & dosificación , Indoles/farmacología , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/prevención & control , Enfermedades por Prión/tratamiento farmacológico , Enfermedades por Prión/prevención & control , Respuesta de Proteína Desplegada/efectos de los fármacos , Adenina/administración & dosificación , Adenina/sangre , Adenina/farmacología , Adenina/uso terapéutico , Administración Oral , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/patología , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Factor 2 Eucariótico de Iniciación/metabolismo , Indoles/sangre , Indoles/uso terapéutico , Ratones , Degeneración Nerviosa/enzimología , Degeneración Nerviosa/patología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fosforilación/efectos de los fármacos , Enfermedades por Prión/enzimología , Enfermedades por Prión/patología , Priones , Biosíntesis de Proteínas/efectos de los fármacos , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , eIF-2 Quinasa/antagonistas & inhibidores , eIF-2 Quinasa/metabolismo
15.
Cancer Res ; 73(6): 1993-2002, 2013 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-23333938

RESUMEN

The unfolded protein response (UPR) is a signal transduction pathway that coordinates cellular adaptation to microenvironmental stresses that include hypoxia, nutrient deprivation, and change in redox status. These stress stimuli are common in many tumors and thus targeting components of the UPR signaling is an attractive therapeutic approach. We have identified a first-in-class, small molecule inhibitor of the eukaryotic initiation factor 2-alpha kinase 3 (EIF2AK3) or PERK, one of the three mediators of UPR signaling. GSK2656157 is an ATP-competitive inhibitor of PERK enzyme activity with an IC(50) of 0.9 nmol/L. It is highly selective for PERK with IC(50) values >100 nmol/L against a panel of 300 kinases. GSK2656157 inhibits PERK activity in cells with an IC(50) in the range of 10-30 nmol/L as shown by inhibition of stress-induced PERK autophosphorylation, eIF2α substrate phosphorylation, together with corresponding decreases in ATF4 and CAAT/enhancer binding protein homologous protein (CHOP) in multiple cell lines. Oral administration of GSK2656157 to mice shows a dose- and time-dependent pharmacodynamic response in pancreas as measured by PERK autophosphorylation. Twice daily dosing of GSK2656157 results in dose-dependent inhibition of multiple human tumor xenografts growth in mice. Altered amino acid metabolism, decreased blood vessel density, and vascular perfusion are potential mechanisms for the observed antitumor effect. However, despite its antitumor activity, given the on-target pharmacologic effects of PERK inhibition on pancreatic function, development of any PERK inhibitor in human subjects would need to be cautiously pursued in cancer patients.


Asunto(s)
Adenina/análogos & derivados , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , eIF-2 Quinasa/antagonistas & inhibidores , Adenina/farmacología , Animales , Femenino , Perfilación de la Expresión Génica , Ratones
16.
ACS Med Chem Lett ; 4(10): 964-8, 2013 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-24900593

RESUMEN

We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.

17.
J Med Chem ; 55(16): 7193-207, 2012 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-22827572

RESUMEN

Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.


Asunto(s)
Adenina/análogos & derivados , Antineoplásicos/síntesis química , Indoles/síntesis química , Pirimidinas/síntesis química , Pirroles/síntesis química , eIF-2 Quinasa/antagonistas & inhibidores , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Indoles/química , Indoles/farmacología , Masculino , Ratones , Ratones Desnudos , Modelos Moleculares , Trasplante de Neoplasias , Fosforilación , Conformación Proteica , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Trasplante Heterólogo
18.
J Med Chem ; 54(6): 1871-95, 2011 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-21341675

RESUMEN

Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.


Asunto(s)
Antineoplásicos/síntesis química , Indazoles/síntesis química , Morfolinas/síntesis química , Piperidinas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Indazoles/química , Indazoles/farmacología , Ratones , Ratones SCID , Modelos Moleculares , Estructura Molecular , Morfolinas/química , Morfolinas/farmacología , Trasplante de Neoplasias , Fosforilación , Piperidinas/química , Piperidinas/farmacología , Unión Proteica , Pirimidinas/química , Pirimidinas/farmacología , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Estereoisomerismo , Relación Estructura-Actividad , Trasplante Heterólogo
19.
ACS Med Chem Lett ; 1(8): 439-42, 2010 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-24900229

RESUMEN

Fragment screening of phosphoinositide-dependent kinase-1 (PDK1) in a biochemical kinase assay afforded hits that were characterized and prioritized based on ligand efficiency and binding interactions with PDK1 as determined by NMR. Subsequent crystallography and follow-up screening led to the discovery of aminoindazole 19, a potent leadlike PDK1 inhibitor with high ligand efficiency. Well-defined structure-activity relationships and protein crystallography provide a basis for further elaboration and optimization of 19 as a PDK1 inhibitor.

20.
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