RESUMO
Ras proteins are among the most frequently mutated drivers in human cancer and remain an elusive pharmaceutical targeting. Previous studies have improved the understanding of Ras structure, processing, and signaling pathways in cancer cells and have opened new possibilities for inhibiting Ras function. In this review we discuss the most recent advances towards inhibiting Ras activity with small molecules, highlighting the two approaches: (i) compounds that bind directly to Ras protein and (ii) inhibitors of the enzymes involved in the post-translational modifications of Ras. In the former, we analyze the most recent contributions in each of the main classes of Ras direct binders, including the different types of nucleotide exchange inhibitors, allosteric compounds, and molecules that interfere with the interaction between Ras and its effectors. In the latter, we examine the compounds that inhibit Ras activation by blocking any of its post-translational modifications. Also, a special focus is made on those molecules that have progressed the farthest from medicinal chemistry and drug development points of view. Finally, the current scene regarding the clinical trials of Ras inhibitors, together with the future promising avenues for further development of the challenging Ras field are reviewed.
Assuntos
Neoplasias/metabolismo , Transdução de Sinais , Proteínas ras/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Descoberta de Drogas , Humanos , Terapia de Alvo Molecular , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/patologia , Ligação Proteica/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Resultado do Tratamento , Proteínas ras/antagonistas & inibidores , Proteínas ras/química , Proteínas ras/genéticaRESUMO
The failure to undergo remyelination is a critical impediment to recovery in multiple sclerosis. Chondroitin sulfate proteoglycans (CSPGs) accumulate at demyelinating lesions creating a nonpermissive environment that impairs axon regeneration and remyelination. Here, we reveal a new role for 2-arachidonoylglycerol (2-AG), the major CNS endocannabinoid, in the modulation of CSPGs deposition in a progressive model of multiple sclerosis, the Theiler's murine encephalomyelitis virus-induced demyelinating disease. Treatment with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-AG degradation in the mouse CNS, modulates neuroinflammation and reduces CSPGs accumulation and astrogliosis around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. Inhibition of 2-AG hydrolysis augments the number of mature oligodendrocytes and increases MBP, leading to remyelination and functional recovery of mice. Our findings establish a mechanism for 2-AG promotion of remyelination with implications in axonal repair in CNS demyelinating pathologies.SIGNIFICANCE STATEMENT The deposition of chondroitin sulfate proteoglycans contributes to the failure in remyelination associated with multiple sclerosis. Here we unveil a new role for 2-arachidonoylglycerol, the major CNS endocannabinoid, in the modulation of chondroitin sulfate proteoglycan accumulation in Theiler's murine encephalomyelitis virus-induced demyelinating disease. The treatment during the chronic phase with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-arachidonoylglycerol degradation in the mouse CNS, modulates neuroinflammation and reduces chondroitin sulfate proteoglycan deposition around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. The increased 2-arachidonoylglycerol tone promotes remyelination in a model of progressive multiple sclerosis ameliorating motor dysfunction.
Assuntos
Ácidos Araquidônicos/farmacologia , Ácidos Araquidônicos/uso terapêutico , Endocanabinoides/farmacologia , Endocanabinoides/uso terapêutico , Glicerídeos/farmacologia , Glicerídeos/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/fisiopatologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/patologia , Proteoglicanas/metabolismo , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Feminino , Camundongos , Esclerose Múltipla/patologia , Neurogênese/efeitos dos fármacosRESUMO
The innate immune response is mediated by primary immune modulators such as cytokines and chemokines that together with immune cells and resident glia orchestrate CNS immunity and inflammation. Growing evidence supports that the endocannabinoid 2-arachidonoylglycerol (2-AG) exerts protective actions in CNS injury models. Here, we used the acute phase of Theiler's virus induced demyelination disease (TMEV-IDD) as a model of acute neuroinflammation to investigate whether 2-AG modifies the brain innate immune responses to TMEV and CNS leukocyte trafficking. 2-AG or the inhibition of its hydrolysis diminished the reactivity and number of microglia at the TMEV injection site reducing their morphological complexity and modulating them towards an anti-inflammatory state via CB2 receptors. Indeed, 2-AG dampened the infiltration of immune cells into the CNS and inhibited their egress from the spleen, resulting in long-term beneficial effects at the chronic phase of the disease. Intriguingly, it is not a generalized action over leukocytes since 2-AG increased the presence and suppressive potency of myeloid derived suppressor cells (MDSCs) in the brain resulting in higher apoptotic CD4+ T cells at the injection site. Together, these data suggest a robust modulatory effect in the peripheral and central immunity by 2-AG and highlight the interest of modulating endogenous cannabinoids to regulate CNS inflammatory conditions.
Assuntos
Ácidos Araquidônicos/metabolismo , Infecções por Cardiovirus/imunologia , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Inflamação/imunologia , Microglia/imunologia , Theilovirus , Animais , Ácidos Araquidônicos/administração & dosagem , Encéfalo/imunologia , Encéfalo/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Infecções por Cardiovirus/patologia , Modelos Animais de Doenças , Endocanabinoides/administração & dosagem , Feminino , Glicerídeos/administração & dosagem , Imunidade Inata/imunologia , Inflamação/patologia , Camundongos , Microglia/patologia , Monoacilglicerol Lipases/antagonistas & inibidores , Monoacilglicerol Lipases/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismoRESUMO
Serotonin (5-HT) modulates key aspects of the immune system. However, its precise function and the receptors involved in the observed effects have remained elusive. Among the different serotonin receptors, 5-HT1A plays an important role in the immune system given its presence in cells involved in both the innate and adaptive immune responses, but its actual levels of expression under different conditions have not been comprehensively studied due to the lack of suitable tools. To further clarify the role of 5-HT1A receptor in the immune system, we have developed a fluorescent small molecule probe that enables the direct study of the receptor levels in native cells. This probe allows direct profiling of the receptor expression in immune cells using flow cytometry. Our results show that important subsets of immune cells including human monocytes and dendritic cells express functional 5-HT1A and that its activation is associated with anti-inflammatory signaling. Furthermore, application of the probe to the experimental autoimmune encephalomyelitis model of multiple sclerosis demonstrates its potential to detect the specific overexpression of the 5-HT1A receptor in CD4+ T cells. Accordingly, the probe reported herein represents a useful tool whose use can be extended to study the levels of 5-HT1A receptor in ex vivo samples of different immune system conditions.
Assuntos
Compostos de Boro/química , Citometria de Fluxo/métodos , Corantes Fluorescentes/química , Receptor 5-HT1A de Serotonina/análise , Animais , Compostos de Boro/síntese química , Técnicas de Química Sintética , Células Dendríticas/química , Corantes Fluorescentes/síntese química , Humanos , Leucócitos Mononucleares/patologia , Camundongos , Monócitos/química , Esclerose Múltipla/patologia , Linfócitos T/químicaRESUMO
Despite more than three decades of intense effort, no anti-Ras therapies have reached clinical application. Contributing to this failure has been an underestimation of Ras complexity and a dearth of structural information. In this regard, recent studies have revealed the highly dynamic character of the Ras surface and the existence of transient pockets suitable for small-molecule binding, opening up new possibilities for the development of Ras modulators. Herein, a novel Ras inhibitor (compound 12) is described that selectively impairs mutated Ras activity in a reversible manner without significantly affecting wild-type Ras, reduces the Ras-guanosine triphosphate (GTP) levels, inhibits the activation of the mitogen-activated protein kinase (MAPK) pathway, and exhibits remarkable cytotoxic activity in Ras-driven cellular models. The use of molecular dynamics simulations and NMR spectroscopy experiments has enabled the molecular bases responsible for the interactions between compound 12 and Ras protein to be explored. The new Ras inhibitor binds partially to the GTP-binding region and extends into the adjacent hydrophobic pocket delimited by switchâ II. Hence, Ras inhibitor 12 could represent a new compound for the development of more efficacious drugs to target Ras-driven cancers; a currently unmet clinical need.
RESUMO
Determination of the targets of a compound remains an essential aspect in drug discovery. A complete understanding of all binding interactions is critical to recognize in advance both therapeutic effects and undesired consequences. However, the complete polypharmacology of many drugs currently in clinical development is still unknown, especially in the case of Gâ protein-coupled receptor (GPCR) ligands. In this work we have developed a chemoproteomic platform based on the use of chemical probes to explore the target profile of a compound in biological systems. As proof of concept, this methodology has been applied to selected ligands of the therapeutically relevant serotonin 5-HT1A and 5-HT6 receptors, and we have identified and validated some of their off-targets. This approach could be extended to other drugs of interest to study the targeted proteome in disease-relevant systems.
Assuntos
Receptor 5-HT1A de Serotonina/química , Receptores Acoplados a Proteínas G/química , Receptores de Serotonina/química , Desenho de Fármacos , Descoberta de Drogas , Humanos , Ligantes , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Serotonina/metabolismoRESUMO
Monoacylglycerol lipase (MAGL) is the enzyme responsible for the inactivation of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibitors show analgesic and tissue-protecting effects in several disease models. However, the few efficient and selective MAGL inhibitors described to date block the enzyme irreversibly, and this can lead to pharmacological tolerance. Hence, additional classes of MAGL inhibitors are needed to validate this enzyme as a therapeutic target. Here we report a potent, selective, and reversible MAGL inhibitor (IC50=0.18â µM) which is active in vivo and ameliorates the clinical progression of a multiple sclerosis (MS) mouse model without inducing undesirable CB1 -mediated side effects. These results support the interest in MAGL as a target for the treatment of MS.
Assuntos
Monoacilglicerol Lipases/antagonistas & inibidores , Esclerose Múltipla/tratamento farmacológico , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , CamundongosRESUMO
The human microbiota plays an important role in human health and disease, through the secretion of metabolites that regulate key biological functions. We propose that microbiota metabolites represent an unexplored chemical space of small drug-like molecules in the search of new hits for drug discovery. Here, we describe the generation of a set of complex chemotypes inspired on selected microbiota metabolites, which have been synthesized using asymmetric organocatalytic reactions. Following a primary screening in CSC models, we identified the novel compound UCM-13369 (4b) whose cytotoxicity was mediated by NPM1. This protein is one of the most frequent mutations of AML, and NPM1-mutated AML is recognized by the WHO as a distinct hematopoietic malignancy. UCM-13369 inhibits NPM1 expression, downregulates the pathway associated with mutant NPM1 C+, and specifically recognizes the C-end DNA-binding domain of NPM1 C+, avoiding the nucleus-cytoplasm translocation involved in the AML tumorological process. The new NPM1 inhibitor triggers apoptosis in AML cell lines and primary cells from AML patients and reduces tumor infiltration in a mouse model of AML with NPM1 C+ mutation. The disclosed phenotype-guided discovery of UCM-13369, a novel small molecule inspired on microbiota metabolites, confirms that CSC death induced by NPM1 inhibition represents a promising therapeutic opportunity for NPM1-mutated AML, a high-mortality disease.
RESUMO
Agonists at cannabinoid receptors, such as the phytocannabinoid Δ(9)-tetrahydrocannabinol, exert a remarkable array of therapeutic effects but are also associated with undesirable psychoactive side effects. Conversely, targeting enzymes that hydrolyze endocannabinoids (eCBs) allows for more precise fine-tuning of cannabinoid receptor signaling, thus providing therapeutic relief with reduced side effects. Here, we report the development and characterization of an inhibitor of eCB hydrolysis, UCM710, which augments both N-arachidonoylethanolamine and 2-arachidonoylglycerol levels in neurons. This compound displays a unique pharmacological profile in that it inhibits fatty acid amide hydrolase and α/ß-hydrolase domain 6 but not monoacylglycerol lipase. Thus, UCM710 represents a novel tool to delineate the therapeutic potential of compounds that manipulate a subset of enzymes that control eCB signaling.
Assuntos
Amidoidrolases/antagonistas & inibidores , Ácidos Araquidônicos/metabolismo , Moduladores de Receptores de Canabinoides/metabolismo , Endocanabinoides , Inibidores Enzimáticos/farmacologia , Glicerídeos/metabolismo , Monoacilglicerol Lipases/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neurônios/metabolismo , Amidoidrolases/metabolismo , Animais , Células COS , Chlorocebus aethiops , Camundongos , Monoacilglicerol Lipases/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Alcamidas Poli-Insaturadas , Receptores de CanabinoidesRESUMO
Receptors made visible: The described biotin-tagged small-molecule probes with excellent affinities for the CB(1) and CB(2) cannabinoid receptors (CB(1)R and CB(2)R) enable direct visualization of these receptors in native cellular systems, including neurons, microglia, and immune cells. This method could overcome some of the limitations of current methodologies and may help to dissect the complexity of the endogenous cannabinoid system.
Assuntos
Canabinoides/farmacologia , Dronabinol/análogos & derivados , Sondas Moleculares/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Animais , Biotina/química , Células Cultivadas , Dronabinol/farmacologia , Citometria de Fluxo , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Simulação de Dinâmica Molecular , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Conformação Proteica , Ratos , Receptor CB1 de Canabinoide/química , Receptor CB2 de Canabinoide/químicaRESUMO
Aging is considered the main risk factor for many chronic diseases that frequently appear at advanced ages. However, the inevitability of this process is being questioned by recent research that suggests that senescent cells have specific features that differentiate them from younger cells and that removal of these cells ameliorates senescent phenotype and associated diseases. This opens the door to the design of tailored therapeutic interventions aimed at reducing and delaying the impact of senescence in life, that is, extending healthspan and treating aging as another chronic disease. Although these ideas are still far from reaching the bedside, it is conceivable that they will revolutionize the way we understand aging in the next decades. In this review, we analyze the main and well-validated cellular pathways and targets related to senescence as well as their implication in aging-associated diseases. In addition, the most relevant small molecules with senotherapeutic potential, with a special emphasis on their mechanism of action, ongoing clinical trials, and potential limitations, are discussed. Finally, a brief overview of alternative strategies that go beyond the small molecule field, together with our perspectives for the future of the field, is provided.
RESUMO
Spinal cord injuries (SCIs) irreversibly disrupt spinal connectivity, leading to permanent neurological disabilities. Current medical treatments for reducing the secondary damage that follows the initial injury are limited to surgical decompression and anti-inflammatory drugs, so there is a pressing need for new therapeutic strategies. Inhibition of the type 2 lysophosphatidic acid receptor (LPA2) has recently emerged as a new potential pharmacological approach to decrease SCI-associated damage. Toward validating this receptor as a target in SCI, we have developed a new series of LPA2 antagonists, among which compound 54 (UCM-14216) stands out as a potent and selective LPA2 receptor antagonist (Emax = 90%, IC50 = 1.9 µM, KD = 1.3 nM; inactive at LPA1,3-6 receptors). This compound shows efficacy in an in vivo mouse model of SCI in an LPA2-dependent manner, confirming the potential of LPA2 inhibition for providing a new alternative for treating SCI.
Assuntos
Receptores de Ácidos Lisofosfatídicos , Traumatismos da Medula Espinal , Animais , Camundongos , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológicoRESUMO
Tolerance development caused by dopamine replacement with l-DOPA and therapeutic drawbacks upon activation of dopaminergic receptors with orthosteric agonists reveal a significant unmet need for safe and effective treatment of Parkinson's disease. In search for selective modulators of the D1 receptor, the screening of a chemical library and subsequent medicinal chemistry program around an identified hit resulted in new synthetic compound 26 [UCM-1306, 2-(fluoromethoxy)-4'-(S-methanesulfonimidoyl)-1,1'-biphenyl] that increases the dopamine maximal effect in a dose-dependent manner in human and mouse D1 receptors, is inactive in the absence of dopamine, modulates dopamine affinity for the receptor, exhibits subtype selectivity, and displays low binding competition with orthosteric ligands. The new allosteric modulator potentiates cocaine-induced locomotion and enhances l-DOPA recovery of decreased locomotor activity in reserpinized mice after oral administration. The behavior of compound 26 supports the interest of a positive allosteric modulator of the D1 receptor as a promising therapeutic approach for Parkinson's disease.
Assuntos
Cocaína , Doença de Parkinson , Animais , Compostos de Bifenilo , Dopamina/metabolismo , Dopaminérgicos , Agonistas de Dopamina/farmacologia , Humanos , Indazóis , Levodopa , Ligantes , Camundongos , Nitrofuranos , Doença de Parkinson/tratamento farmacológico , Receptores Dopaminérgicos , Receptores de Dopamina D1/agonistasRESUMO
Peptidic agonists of the glucagon-like peptide-1 receptor (GLP-1R) have gained a prominent role in the therapy of type-2 diabetes and are being considered for reducing food intake in obesity. Potential advantages of small molecules acting as positive allosteric modulators (PAMs) of GLP-1R, including oral administration and reduced unwanted effects, could improve the utility of this class of drugs. Here, we describe the discovery of compound 9 (4-{[1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)piperidin-3-yl]methyl}morpholine, V-0219) that exhibits enhanced efficacy of GLP-1R stimulation, subnanomolar potency in the potentiation of insulin secretion, and no significant off-target activities. The identified GLP-1R PAM shows a remarkable in vivo activity, reducing food intake and improving glucose handling in normal and diabetic rodents. Enantioselective synthesis revealed oral efficacy for (S)-9 in animal models. Compound 9 behavior bolsters the interest of a small-molecule PAM of GLP-1R as a promising therapeutic approach for the increasingly prevalent obesity-associated diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Administração Oral , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Obesidade/tratamento farmacológico , Peptídeos/uso terapêuticoRESUMO
Cell division protein FtsZ can form single-stranded filaments with a cooperative behavior by self-switching assembly. Subsequent condensation and bending of FtsZ filaments are important for the formation and constriction of the cytokinetic ring. PC190723 is an effective bactericidal cell division inhibitor that targets FtsZ in the pathogen Staphylococcus aureus and Bacillus subtilis and does not affect Escherichia coli cells, which apparently binds to a zone equivalent to the binding site of the antitumor drug taxol in tubulin (Haydon, D. J., Stokes, N. R., Ure, R., Galbraith, G., Bennett, J. M., Brown, D. R., Baker, P. J., Barynin, V. V., Rice, D. W., Sedelnikova, S. E., Heal, J. R., Sheridan, J. M., Aiwale, S. T., Chauhan, P. K., Srivastava, A., Taneja, A., Collins, I., Errington, J., and Czaplewski, L. G. (2008) Science 312, 1673-1675). We have found that the benzamide derivative PC190723 is an FtsZ polymer-stabilizing agent. PC190723 induced nucleated assembly of Bs-FtsZ into single-stranded coiled protofilaments and polymorphic condensates, including bundles, coils, and toroids, whose formation could be modulated with different solution conditions. Under conditions for reversible assembly of Bs-FtsZ, PC190723 binding reduced the GTPase activity and induced the formation of straight bundles and ribbons, which was also observed with Sa-FtsZ but not with nonsusceptible Ec-FtsZ. The fragment 2,6-difluoro-3-methoxybenzamide also induced Bs-FtsZ bundling. We propose that polymer stabilization by PC190723 suppresses in vivo FtsZ polymer dynamics and bacterial division. The biochemical action of PC190723 on FtsZ parallels that of the microtubule-stabilizing agent taxol on the eukaryotic structural homologue tubulin. Both taxol and PC190723 stabilize polymers against disassembly by preferential binding to each assembled protein. It is yet to be investigated whether both ligands target structurally related assembly switches.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Proteínas do Citoesqueleto/metabolismo , Excipientes/farmacologia , Piridinas/farmacologia , Tiazóis/farmacologia , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/enzimologia , Bacillus subtilis/crescimento & desenvolvimento , Sítios de Ligação , Divisão Celular/efeitos dos fármacosRESUMO
Bacterial resistance to antibiotics makes previously manageable infections again disabling and lethal, highlighting the need for new antibacterial strategies. In this regard, inhibition of the bacterial division process by targeting key protein FtsZ has been recognized as an attractive approach for discovering new antibiotics. Binding of small molecules to the cleft between the N-terminal guanosine triphosphate (GTP)-binding and the C-terminal subdomains allosterically impairs the FtsZ function, eventually inhibiting bacterial division. Nonetheless, the lack of appropriate chemical tools to develop a binding screen against this site has hampered the discovery of FtsZ antibacterial inhibitors. Herein, we describe the first competitive binding assay to identify FtsZ allosteric ligands interacting with the interdomain cleft, based on the use of specific high-affinity fluorescent probes. This novel assay, together with phenotypic profiling and X-ray crystallographic insights, enables the identification and characterization of FtsZ inhibitors of bacterial division aiming at the discovery of more effective antibacterials.
Assuntos
Antibacterianos/química , Proteínas de Bactérias/metabolismo , Proteínas do Citoesqueleto/metabolismo , Sítio Alostérico , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/farmacologia , Cristalografia por Raios X , Proteínas do Citoesqueleto/antagonistas & inibidores , Polarização de Fluorescência , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Ligantes , Testes de Sensibilidade Microbiana , Ligação Proteica , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismo , Relação Estrutura-AtividadeRESUMO
Hutchinson-Gilford progeria syndrome (HGPS, progeria) is a rare genetic disease characterized by premature aging and death in childhood for which there were no approved drugs for its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of lonafarnib in patients are limited, highlighting the need for new therapeutic strategies. Here, we validate the enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as a new therapeutic target for progeria with the development of a new series of potent inhibitors of this enzyme that exhibit an excellent antiprogeroid profile. Among them, compound UCM-13207 significantly improved the main hallmarks of progeria. Specifically, treatment of fibroblasts from progeroid mice with UCM-13207 delocalized progerin from the nuclear membrane, diminished its total protein levels, resulting in decreased DNA damage, and increased cellular viability. Importantly, these effects were also observed in patient-derived cells. Using the Lmna G609G/G609G progeroid mouse model, UCM-13207 showed an excellent in vivo efficacy by increasing body weight, enhancing grip strength, extending lifespan by 20%, and decreasing tissue senescence in multiple organs. Furthermore, UCM-13207 treatment led to an improvement of key cardiovascular hallmarks such as reduced progerin levels in aortic and endocardial tissue and increased number of vascular smooth muscle cells (VSMCs). The beneficial effects go well beyond the effects induced by other therapeutic strategies previously reported in the field, thus supporting the use of UCM-13207 as a new treatment for progeria.
RESUMO
Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA1) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA1 agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA1 receptor agonist described so far (Emax = 118%, EC50 = 0.24 µM, KD = 19.6 nM; inactive at autotaxin and LPA2-6 receptors). This compound induces characteristic LPA1-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.
Assuntos
Analgésicos/química , Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Receptores de Ácidos Lisofosfatídicos/agonistas , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Descoberta de Drogas , Feminino , Humanos , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/uso terapêutico , Camundongos Endogâmicos C57BL , Modelos Moleculares , Neuralgia/metabolismo , Percepção da Dor/efeitos dos fármacos , Ratos Wistar , Receptores de Ácidos Lisofosfatídicos/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismoRESUMO
Blockade of Ras activity by inhibiting its post-translational methylation catalyzed by isoprenylcysteine carboxylmethyltransferase (ICMT) has been suggested as a promising antitumor strategy. However, the paucity of inhibitors has precluded the clinical validation of this approach. In this work we report a potent ICMT inhibitor, compound 3 [UCM-1336, IC50 = 2 µM], which is selective against the other enzymes involved in the post-translational modifications of Ras. Compound 3 significantly impairs the membrane association of the four Ras isoforms, leading to a decrease of Ras activity and to inhibition of Ras downstream signaling pathways. In addition, it induces cell death in a variety of Ras-mutated tumor cell lines and increases survival in an in vivo model of acute myeloid leukemia. Because ICMT inhibition impairs the activity of the four Ras isoforms regardless of its activating mutation, compound 3 surmounts many of the common limitations of available Ras inhibitors described so far. In addition, these results validate ICMT as a valuable target for the treatment of Ras-driven tumors.