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Based on knowledge of kinase switch-control inhibition and using a combination of structure-based drug design and standard medicinal chemistry principles, we identified a novel series of dihydropyrimidone-based CSF1R kinase inhibitors displaying exquisite selectivity for CSF1R versus a large panel of kinases and non-kinase protein targets. Starting with lead compound 3, an SAR optimization campaign led to the discovery of vimseltinib (DCC-3014; compound 20) currently undergoing clinical evaluation for the treatment of Tenosynovial Giant Cell Tumor (TGCT), a locally aggressive benign tumor associated with substantial morbidity. 2021 Elsevier ltd. All rights reserved.
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Antineoplásicos , Tumor de Células Gigantes de las Vainas Tendinosas , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Receptor DCC , Tumor de Células Gigantes de las Vainas Tendinosas/tratamiento farmacológico , Tumor de Células Gigantes de las Vainas Tendinosas/patología , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras , Receptor de Factor Estimulante de Colonias de MacrófagosRESUMEN
Based on the structure of an early lead identified in Deciphera's proprietary compound collection of switch control kinase inhibitors and using a combination of medicinal chemistry guided structure activity relationships and structure-based drug design, a novel series of potent acyl urea-based CSF1R inhibitors was identified displaying high selectivity for CSF1R versus the other members of the Type III receptor tyrosine kinase (RTK) family members (KIT, PDGFR-α, PDGFR-ß, and FLT3), VEGFR2 and MET. Based on in vitro biology, in vitro ADME and in vivo PK/PD studies, compound 10 was selected as an advanced lead for Deciphera's CSF1R research program.
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Proteínas Tirosina Quinasas Receptoras , Urea , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , Relación Estructura-Actividad , Urea/química , Urea/farmacologíaRESUMEN
BACKGROUND: Wrinkles and extracellular matrix (ECM) loss are common signs of skin aging and are thought to be the result of damage caused by reactive oxygen species (ROS); ROS induces an imbalance between ECM degradation and production. OBJECTIVES: In this study, we evaluate soy peptides (SP) and collagen peptides (CP), alone and in combination, for their ability to inhibit ROS formation and increase ECM gene expression in order to ameliorate the signs of skin aging. METHODS: Using tert-Butyl hydroperoxide (t-BuOOH)-treated dermal fibroblasts, we explored the potential of CP and SP to inhibit ROS formation by flow cytometry, as well as their effect on ECM component genes by real-time quantitative PCR. In addition, we examined the effect of CP and SP on UVA irradiated fibroblasts in a 3D collagen lattice model that measured contractility. RESULTS: The results showed that the combination of CP and SP synergistically reduces ROS formation. This combination also increased expression of collagen I, collagen II, elastin, and fibronectin in t-BuOOH-treated or untreated dermal fibroblasts. In the UVA-treated 3D collagen lattice model, the results show that CP and SP significantly improved fibroblast contractility when compared to UVA control (P < 0.05). CONCLUSIONS: In conclusion, CP and SP attenuate the loss of contractility due to UVA damage, inhibit t-BuOOH-induced ROS formation, and improve expression of ECM component genes.
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Antioxidantes , Envejecimiento de la Piel , Antioxidantes/farmacología , Células Cultivadas , Colágeno , Fibroblastos , Humanos , Péptidos/farmacología , Piel , Rayos Ultravioleta/efectos adversosRESUMEN
Herbal pairs are used as a bridge between single herb and polyherbal formulas in Traditional Chinese Medicine (TCM) to provide rationale for complicated TCM formulas. The effectiveness and rationality of TCM herbal pairs have been widely applied as a strategy for dietary supplements. However, due to the complexity of the phytochemistry of individual and combinations of herbal materials, it is difficult to reveal their effective and synergistic mechanisms from a molecular or systematic point of view. In order to address this question, UPLC-Q-TOF/MS analysis and System Pharmacology tools were applied to explore the mechanism of action, using a White Peony (Paeoniae Radix Alba) and Licorice (Glycyrrhizae Radix et Rhizoma)-based dietary supplement. A total of sixteen chemical constituents of White Peony and Licorice were isolated and identified, which interact with 73 liver protection-related targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed along with network analysis. Results showed that the synergistic mechanism of the White Peony and Licorice herbal pair was associated with their coregulation of bile secretion and ABC transporter pathways. In addition, Licorice exhibits a specific response to drug and xenobiotic metabolism pathways, whereas White Peony responds to Toll-like receptor signaling, C-type lectin receptor signaling, IL-17 signaling, and TNF signaling pathways, resulting in the prevention of hepatocyte apoptosis and the reduction of immune and inflammation-mediated liver damage. These findings suggest that a White Peony and Licorice herbal pair supplement would have a liver-protecting benefit through complimentary and synergistic mechanisms. This approach provides a new path to explore herbal compatibility in dietary supplements derived from TCM theory.
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Novel coronaviruses (CoV) have emerged periodically around the world in recent years. The recurrent spreading of CoVs imposes an ongoing threat to global health and the economy. Since no specific therapy for these CoVs is available, any beneficial approach (including nutritional and dietary approach) is worth investigation. Based on recent advances in nutrients and phytonutrients research, a novel combination of vitamin C, curcumin and glycyrrhizic acid (VCG Plus) was developed that has potential against CoV infection. System biology tools were applied to explore the potential of VCG Plus in modulating targets and pathways relevant to immune and inflammation responses. Gene target acquisition, gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment were conducted consecutively along with network analysis. The results show that VCG Plus can act on 88 hub targets which are closely connected and associated with immune and inflammatory responses. Specifically, VCG Plus has the potential to regulate innate immune response by acting on NOD-like and Toll-like signaling pathways to promote interferons production, activate and balance T-cells, and regulate the inflammatory response by inhibiting PI3K/AKT, NF-κB and MAPK signaling pathways. All these biological processes and pathways have been well documented in CoV infections studies. Therefore, our findings suggest that VCG Plus may be helpful in regulating immune response to combat CoV infections and inhibit excessive inflammatory responses to prevent the onset of cytokine storm. However, further in vitro and in vivo experiments are warranted to validate the current findings with system biology tools. Our current approach provides a new strategy in predicting formulation rationale when developing new dietary supplements.
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Ácido Ascórbico/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Curcumina/uso terapéutico , Ácido Glicirrínico/uso terapéutico , Inmunidad Innata/efectos de los fármacos , Inflamación/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ácido Ascórbico/farmacología , Coronavirus , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/virología , Curcuma/química , Curcumina/farmacología , Citocinas/metabolismo , Combinación de Medicamentos , Sistemas de Liberación de Medicamentos , Ontología de Genes , Glycyrrhiza/química , Ácido Glicirrínico/farmacología , Humanos , Interferones/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Transducción de Señal , Biología de Sistemas , Linfocitos T/metabolismo , Vitaminas/farmacología , Vitaminas/uso terapéuticoRESUMEN
PURPOSE: Chronic gastritis is observed in almost half world population. Traditional medications against chronic gastritis might produce adverse effects, so alternative nutritional strategies are needed to prevent the aggravation of gastric mucosal damage. The aim of this study is to evaluate the protective effect of the combination of wheat peptides and fucoidan (WPF) on adults diagnosed with chronic superficial gastritis in a randomized, double-blind, placebo-controlled clinical trial. METHODS: Participants were randomized to receive WPF (N = 53) or placebo (N = 53) once daily for 45 days. Pathological grading of gastric mucosal damage was scored using gastroscopy. Fecal samples were collected for the determination of calprotectin, short chain fatty acids (SCFA) levels and metagenomics analysis. Questionnaires for self-reported gastrointestinal discomforts, life quality and food frequency were collected throughout the study. RESULTS: WPF intervention reduced gastric mucosal damage in 70% subjects (P < 0.001). Significantly less stomach pain (P < 0.001), belching (P = 0.028), bloating (P < 0.001), acid reflux (P < 0.001), loss of appetite (P = 0.021), increased food intake (P = 0.020), and promoted life quality (P = 0.014) were reported in the WPF group. WPF intervention significantly decreased fecal calprotectin level (P = 0.003) while slightly increased fecal SCFAs level (P = 0.092). In addition, we found altered microbiota composition post-intervention with increased Bifidobacterium pseudocatenulatum (P = 0.032), Eubacterium siraeum (P = 0.036), Bacteroides intestinalis (P = 0.024) and decreased Prevotella copri (P = 0.055). CONCLUSIONS: WPF intervention could be utilized as a nutritional alternative to mitigate the progression of chronic gastritis. Furthermore, WPF played an important role in altering gut microbial profile and SCFA production, which might benefit the lower gastrointestinal tract.
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Antiulcerosos/farmacología , Gastritis/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Péptidos/farmacología , Polisacáridos/farmacología , Triticum , Adulto , China , Enfermedad Crónica , Método Doble Ciego , Heces/microbiología , Femenino , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/microbiología , Humanos , Masculino , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To investigate the development of a minimal traditional Chinese medicine (TCM) formula using selected TCM ingredients and evaluating their biological activity with bone-specific in vitro tests. Finally, determining if the minimal formula can maintain bone mineral density (BMD) in a low bone mass (LBM)/osteoporosis (OP) model system. METHODS AND RESULTS: Sixteen different TCM plant extracts were tested for estrogenic, osteogenic and osteoclastic activities. Despite robust activation of the full-length estrogen receptors α and ß by Psoralea corylifolia and Epimedium brevicornu, these extracts do not activate the isolated estrogen ligand binding domains (LBD) of either ERα or ERß; estrogen (17-ß estradiol) fully activates the LBD of ERα and ERß. E. brevicornu and Drynaria fortunei extracts activated cyclic AMP response elements (CRE) individually and when combined these ingredients stimulated the production of osteoblastic markers Runx2 and Bmp4 in MC3T3-E1 cells. E. brevicornu, Salvia miltiorrhiza, and Astragalus onobrychis extracts inhibited the Il-1ß mediated activation of NF-κß and an E. brevicornu/D. fortunei combination inhibited the development of osteoclasts from precursor cells. Further, a minimal formula containing the E. brevicornu/D. fortunei combination with or without a third ingredient (S. miltiorrhiza, Angelica sinensis, or Lycium barbarum) maintained bone mineral density (BMD) similar to an estradiol-treated control group in the ovariectomized rat; a model LBM/OP system. CONCLUSION: A minimal formula consisting of TCM plant extracts that activate CRE and inhibit of NF-κß activation, but do not behave like estrogen, maintain BMD in a LBM/OP model system.
RESUMEN
Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a "switch-control" kinase inhibitor that forces the activation loop (or activation "switch") into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.
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Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Animales , Células CHO , Línea Celular , Línea Celular Tumoral , Cricetulus , Resistencia a Antineoplásicos/genética , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Células HCT116 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Mutación/efectos de los fármacos , Mutación/genéticaRESUMEN
Gastritis or peptic ulcer is believed to affect about half of people worldwide. Traditional medications can lead to adverse effects, therefore, alternative nutritional strategies are needed to prevent the development of gastric mucosal damage. A novel combination of two food-grade ingredients, wheat peptides and fucoidan (WPF), was prepared to treat male Sprague Dawley rats for 30 days before gastric mucosal damage was induced by oral administration of ethanol. The serum levels of biomarkers were determined by enzyme-linked immunosorbent assay. Biomarkers in stomach tissue were analyzed using immunohistochemistry. In addition, human gastric epithelial cell line (GES-1) was used to investigate protein expression by Western blot. WPF could attenuate ethanol-induced gastric mucosal damage in an inverse dose-dependent manner, with both ulcer index and pathological index improved. WPF increased superoxide dismutase level and decreased malondialdehyde level. WPF also decreased the levels of interleukin-8, platelet-activating factor, and Caspase 3, while increasing the levels of prostaglandin E-2, epidermal growth factor (EGF), and EGF receptor (EGFR). Furthermore, phosphorylation of EGFR and extracellular signal-regulated kinases was induced by WPF in GES-1 cells. In conclusion, the novel combination of wheat peptides and fucoidan attenuated ethanol-induced gastric mucosal damage in rats through anti-oxidant, anti-inflammatory, and pro-survival mechanisms.
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Antiinflamatorios/farmacología , Antioxidantes/farmacología , Etanol , Mucosa Gástrica/efectos de los fármacos , Proteínas de Plantas/farmacología , Polisacáridos/farmacología , Hidrolisados de Proteína/farmacología , Úlcera Gástrica/prevención & control , Animales , Antiinflamatorios/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Biomarcadores/sangre , Línea Celular , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Receptores ErbB/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Humanos , Masculino , Fosforilación , Proteínas de Plantas/aislamiento & purificación , Hidrolisados de Proteína/aislamiento & purificación , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Úlcera Gástrica/sangre , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/patología , Factores de Tiempo , Triticum/químicaRESUMEN
Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2Hi/Vegf-AHi macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by protumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients. Mol Cancer Ther; 16(11); 2486-501. ©2017 AACR.
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Neoplasias de la Mama/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Pirazoles/farmacología , Piridinas/farmacología , Quinolinas/farmacología , Receptor TIE-2/antagonistas & inhibidores , Angiopoyetinas/antagonistas & inhibidores , Angiopoyetinas/genética , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Ratones , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Quinolinas/uso terapéutico , Receptor TIE-2/genética , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood-brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases.
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Aminopiridinas/farmacología , Anilidas/farmacología , Resistencia a Antineoplásicos , Neovascularización Patológica , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Receptor TIE-2/antagonistas & inhibidores , Microambiente Tumoral , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Aminopiridinas/química , Anilidas/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Bevacizumab/química , Bevacizumab/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Diseño de Fármacos , Quimioterapia Combinada , Femenino , Factor de Crecimiento de Hepatocito/metabolismo , Humanos , Concentración 50 Inhibidora , Melanoma Experimental , Ratones , Modelos Moleculares , Conformación Molecular , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-met/química , Proteínas Proto-Oncogénicas c-met/metabolismo , Receptor TIE-2/metabolismo , Proteínas Recombinantes , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.
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Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Pirimidinas/química , Pirimidinas/farmacología , Proteínas ras/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Línea Celular Tumoral/efectos de los fármacos , Técnicas de Química Sintética , Perros , Femenino , Semivida , Humanos , Masculino , Ratones Desnudos , Terapia Molecular Dirigida , Mutación , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/farmacocinética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-raf/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas ras/genéticaRESUMEN
Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead "switch-control" inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph(+) leukemia.
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Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Proteínas de Fusión bcr-abl/química , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos BALB C , Conformación Proteica , Proteínas Tirosina Quinasas/químicaRESUMEN
Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38-alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38-alpha kinase.
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Adenosina Trifosfato/química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Compuestos de Fenilurea/química , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Células HeLa , Humanos , Cinética , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/farmacología , Fosforilación , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
The inhibition of the cytosolic isoenzyme BCAT that is expressed specifically in neuronal tissue is likely to be useful for the treatment of neurodegenerative and other neurological disorders where glutamatergic mechanisms are implicated. Compound 2 exhibited an IC50 of 0.8 microM in the hBCATc assays; it is an active and selective inhibitor. Inhibitor 2 also blocked calcium influx into neuronal cells following inhibition of glutamate uptake, and demonstrated neuroprotective efficacy in vivo. SAR, pharmacology, and the crystal structure of hBCATc with inhibitor 2 are described.