RESUMEN
The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti-PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly.
Asunto(s)
Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Receptores CXCR4/antagonistas & inhibidores , Animales , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Dietilnitrosamina/administración & dosificación , Dietilnitrosamina/toxicidad , Sinergismo Farmacológico , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/inmunología , Neoplasias Hepáticas Experimentales/patología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Ratones , Simulación del Acoplamiento Molecular , Ratas , Receptores CXCR4/metabolismo , Transducción de Señal/efectos de los fármacos , Sorafenib/farmacología , Sorafenib/uso terapéutico , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging. METHODS: Hesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging. RESULTS: Three discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age. CONCLUSIONS: Our findings indicate that a Cisd2 activator, hesperetin, represents a promising and broadly effective translational approach to slowing down aging and promoting longevity via the activation of Cisd2.
Asunto(s)
Longevidad , Proteínas del Tejido Nervioso , Envejecimiento/genética , Animales , Proteínas Relacionadas con la Autofagia , Hesperidina , Humanos , Longevidad/genética , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genéticaRESUMEN
CXCR4 antagonists have been claimed to reduce mortality after myocardial infarction in myocardial infarction (MI) animals, presumably due to suppressing inflammatory responses caused by myocardial ischemia-reperfusion injury, thus, subsequently facilitating tissue repair and cardiac function recovery. This study aims to determine whether a newly designed CXCR4 antagonist DBPR807 could exert better vascular-protective effects than other clinical counterparts (e.g., AMD3100) to alleviate cardiac damage further exacerbated by reperfusion. Consequently, we find that instead of traditional continuous treatment or multiple-dose treatment at different intervals of time, a single-dose treatment of DBPR807 before reperfusion in MI animals could attenuate inflammation via protecting oxidative stress damage and preserve vascular/capillary density and integrity via mobilizing endothelial progenitor cells, leading to a desirable fibrosis reduction and recovery of cardiac function, as evaluated with the LVEF (left ventricular ejection fraction) in infarcted hearts in rats and mini-pigs, respectively. Thus, it is highly suggested that CXCR4 antagonists should be given at a single high dose prior to reperfusion to provide the maximal cardiac functional improvement. Based on its favorable efficacy and safety profiles indicated in tested animals, DBPR807 has a great potential to serve as an adjunctive medicine for percutaneous coronary intervention (PCI) therapies in acute MI patients.
Asunto(s)
Infarto del Miocardio , Daño por Reperfusión Miocárdica , Intervención Coronaria Percutánea , Receptores CXCR4 , Animales , Infarto del Miocardio/terapia , Daño por Reperfusión Miocárdica/etiología , Ratas , Receptores CXCR4/antagonistas & inhibidores , Volumen Sistólico , Porcinos , Porcinos Enanos , Función Ventricular IzquierdaRESUMEN
In an effort to develop new cancer therapeutics, we have reported clinical candidate BPR1K871 (1) as a potentanticancercompound in MOLM-13 and MV4-11 leukemia models, as well as in colorectal and pancreatic animal models. As BPR1K871 lacks oral bioavailability, we continued searching for orally bioavailable analogs through drug-like property optimization. We optimized both the physicochemical properties (PCP) as well as in vitro rat liver microsomal stability of 1, with concomitant monitoring of aurora kinase enzyme inhibition as well as cellular anti-proliferative activity in HCT-116 cell line. Structural modification at the 6- and 7-position of quinazoline core of 1 led to the identification of 34 as an orally bioavailable (F% = 54) multi-kinase inhibitor, which exhibits potent anti-proliferative activity against various cancer cell lines. Quinazoline 34 is selected as a promising oral lead candidate for further preclinical evaluation.
Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasas/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Aurora Quinasas/metabolismo , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Masculino , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Quinazolinas/administración & dosificación , Quinazolinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Sodium-dependent glucose co-transporter 2 (SGLT2) inhibition has been demonstrated to efficiently control hyperglycemia via an insulin secretion-independent pathway. The unique mode of action eliminates the risk of hypoglycemia and makes SGLT2 inhibitors an attractive option for the treatment of type 2 diabetes. In a continuation of our previous studies on SGLT2 inhibitors bearing different sugar moieties, sixteen new N-glucosyl indole derivatives were designed, synthesized, and evaluated for their inhibitory activity against hSGLT2. Of these sixteen, acethydrazide-containing N-glucosyl indole 9d was found to be the most potent SGLT2 inhibitor, and caused a significant elevation in urine glucose excretion in rats at 50â¯mg/kg, relative to the vehicle control.
Asunto(s)
Glucósidos/farmacología , Indoles/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Animales , Compuestos de Bencidrilo/farmacología , Células CHO , Cricetulus , Glucósidos/síntesis química , Glucósidos/química , Glucósidos/farmacocinética , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacocinética , Estructura Molecular , Ratas Sprague-Dawley , Inhibidores del Cotransportador de Sodio-Glucosa 2/síntesis química , Inhibidores del Cotransportador de Sodio-Glucosa 2/química , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , Relación Estructura-ActividadRESUMEN
Correction for '2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition' by Kunal Nepali et al., Org. Biomol. Chem., 2016, 14, 716-723.
RESUMEN
Indoleamine 2,3-dioxygenase is a heme-containing enzyme implicated in the down regulation of the anti-tumor immune response, and considered a promising anti-cancer drug target. Several pharmaceutical companies, including Pfizer, Merck, and Bristol-Myers Squibb, are known to be in pursuit of IDO inhibitors, and Incyte recently reported good results in the phase II clinical trial of the IDO inhibitor Epacadostat. In previous work, we developed a series of IDO inhibitors based on a sulfonylhydrazide core structure, and explored how they could serve as potent IDO inhibitors with good drug profiles. Herein, we disclose the development of the 4-bromophenylhydrazinyl benzenesulfonylphenylurea 5k, a potent IDO inhibitor which demonstrated 25% tumor growth inhibition in a murine CT26 syngeneic model on day 18 with 100â¯mg/kg oral administration twice daily, and a 30% reduction in tumor weight. Pharmacodynamic testing of 5k found it to cause a 25% and 21% reduction in kyn/trp ratio at the plasma and tumor, respectively. In the CT26 tumor model, 5k was found to slightly increase the percentage of CD3+ T cells and lymphocyte responsiveness, indicating that 5k may have potential in modulating anti-tumor immunity. These data suggest 5k to be worthy of further investigation in the development of anti-tumor drugs.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Sulfonas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/aislamiento & purificación , Complejo CD3/análisis , Complejo CD3/aislamiento & purificación , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/químicaRESUMEN
A series of zinc(II) dipicolylamine (ZnDPA)-based drug conjugates have been synthesized to probe the potential of phosphatidylserine (PS) as a new antigen for small molecule drug conjugate (SMDC) development. Using in vitro cytotoxicity and plasma stability studies, PS-binding assay, in vivo pharmacokinetic studies, and maximum tolerated dose profiles, we provided a roadmap and the key parameters required for the development of the ZnDPA based drug conjugate. In particular, conjugate 24 induced tumor regression in the COLO 205 xenograft model and exhibited a more potent antitumor effect with a 70% reduction of cytotoxic payload compared to that of the marketed irinotecan when dosed at the same regimen. In addition to the validation of PS as an effective pharmacodelivery target for SMDC, our work also provided the foundation that, if applicable, a variety of therapeutic agents could be conjugated in the same manner to treat other PS-associated diseases.
Asunto(s)
Antineoplásicos/farmacocinética , Inmunoconjugados/uso terapéutico , Terapia Molecular Dirigida/métodos , Compuestos Organometálicos/inmunología , Fosfatidilserinas/inmunología , Ácidos Picolínicos/inmunología , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral , Humanos , Inmunoconjugados/química , Inmunoconjugados/farmacocinética , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Fosfatidilserinas/metabolismo , Ácidos Picolínicos/síntesis química , Ácidos Picolínicos/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The authors investigated the pharmacology and signaling pathways of the opioid receptors modulated by compound 1, 1-(2,4-dibromophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one. METHODS: In vitro studies of compound 1 were assessed by using a radioligand-binding assay (n = 3), a cyclic adenosine monophosphate assay (n = 3), a ß-arrestin assay (n = 3), an internalization assay (n = 3), and an immunohistochemistry (n = 8). In vivo studies of compound 1 were characterized using a tail-flick test (n = 5 to 6), tail-clip test (n = 7), von Frey hair test (n = 5), and charcoal meal test (n = 5). RESULTS: Compound 1 elicited robust effects in µ-opioid (mean ± SD; binding affinity: 15 ± 2 nM; cyclic adenosine monophosphate assay: 24 ± 6 nM), δ-opioid (82 ± 7 nM; 1.9 ± 0.1 µM), and κ-opioid (76 ± 9 nM; 1.4 ± 0.5 µM) receptor-expressing cells. Compound 1 acts as a full agonist of ß-arrestin-2 recruitment in µ-opioid (1.1 ± 0.3 µM) and δ-opioid (9.7 ± 1.9 µM) receptor-expressing cells. Compound 1 caused less gastrointestinal dysfunction (charcoal meal test: morphine: 82 ± 5%; compound 1: 42 ± 5%) as well as better antinociception in mechanical pain hypersensitivity (tail-clip test: morphine: 10 ± 3 s; compound 1: 19 ± 1 s) and in cancer-induced pain (von Frey hair test: morphine: 0.1 ± 0.1 g; compound 1: 0.3 ± 0.1 g) than morphine at equi-antinociceptive doses. CONCLUSIONS: Compound 1 produced antinociception with less gastrointestinal dysfunction than morphine.
Asunto(s)
Enfermedades Gastrointestinales/inducido químicamente , Indazoles/farmacología , Morfina , Receptores Opioides/agonistas , Analgésicos Opioides/farmacología , Animales , Modelos Animales de Enfermedad , Enfermedades Gastrointestinales/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
OBJECTIVES: Enterovirus 71 (EV-A71) is an important pathogen that can cause severe neurological symptoms and even death. Our aim was to identify potent anti-EV-A71 compounds and study their underlying mechanisms and in vivo activity. METHODS: We identified a potent imidazolidinone derivative (abbreviated to PR66) as an inhibitor of EV-A71 infection from the screening of compounds and subsequent structure-based modification. Time-course treatments and resistant virus selection of PR66 were employed to study the mode of mechanism of PR66. In vivo activity of PR66 was tested in the ICR strain of new-born mice challenged with EV-A71/4643/MP4. RESULTS: PR66 could impede the uncoating process during viral infection via interaction with capsid protein VP1, as shown by a resistant virus selection assay. Using site-directed mutagenesis, we confirmed that a change from valine to phenylalanine in the 179th amino acid residue of the cDNA-derived resistant virus resulted in resistance to PR66. PR66 increased the virion stability of WT viruses, but not the PR66-resistant mutant, in a particle stability thermal release assay. We further showed that PR66 had excellent anti-EV-A71 activity in an in vivo mouse model of disease, with a dose-dependent increase in survival rate and in protection against virus-induced hind-limb paralysis following oral or intraperitoneal administration. This was associated with reductions of viral titres in brain and muscle tissues. CONCLUSIONS: We demonstrated here for the first time that an imidazolidinone derivative (PR66) could protect against EV-A71-induced neurological symptoms in vivo by suppressing EV-A71 replication. This involved binding to and restricting viral uncoating.
Asunto(s)
Antivirales/metabolismo , Antivirales/farmacología , Cápside/efectos de los fármacos , Enterovirus Humano A/efectos de los fármacos , Animales , Antivirales/aislamiento & purificación , Línea Celular , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Infecciones por Enterovirus/tratamiento farmacológico , Infecciones por Enterovirus/virología , Humanos , Concentración 50 Inhibidora , Ratones Endogámicos ICR , Análisis de SupervivenciaRESUMEN
Oxycodone has been used clinically for over 90 years. While it is known that it exhibits low affinity for the multiple opioid receptors, whether its pharmacological activities are due to oxycodone activation of the opioid receptor type or due to its active metabolite (oxymorphone) that exhibits high affinity for the mu-opioid receptors remains unresolved. Ross and Smith (1997) reported the antinociceptive effects of oxycodone (171nmol, i.c.v.) are induced by putative kappa-opioid receptors in SD rat while others have reported oxycodone activities are due to activation of mu- and/or delta-opioid receptors. In this study, using male mu-opioid receptor knock-out (MOR-KO) mice, we examined whether delta-opioid receptor was involved in oxycodone antinociception. Systemic subcutaneous (s.c.) administration of oxycodone (above 40mg/kg) could induce a small but significant antinociceptive effect in MOR-KO mice by the tail flick test. Delta-opioid receptor antagonist (naltrindole, 10mg/kg or 20mg/kg, i.p.) could block this effect. When oxycodone was injected directly into the brain of MOR-KO mice by intracerebroventricular (i.c.v.) route, oxycodone at doses of 50nmol or higher could induce similar level of antinociceptive responses to those observed in wild type mice at the same doses by i.c.v. Delta-opioid receptor antagonists (naltrindole at 10nmol or ICI 154,129 at 20µg) completely blocked the supraspinal antinociceptive effect of oxycodone in MOR-KO mice. Such oxycodone antinociceptive responses were probably not due to its active metabolites oxymorphone because (a) the relative low level of oxymorphone was found in the brain after systemically or centrally oxycodone injection using LC/MS/MS analysis; (b) oxymorphone at a dose that mimics the level detected in the mice brain did not show any significant antinocieption effect; (c) oxycodone exhibits equal potency as oxymorphone albeit being a partial agonist in regulating [Ca(2+)]I transients in a clonal cell line expressing high level of mu-opioid receptor. These data suggest that oxycodone by itself can activate both the mu- and delta-opioid receptors and that delta-opioid receptors may contribute to the central antinociceptive effect of oxycodone in mice.
Asunto(s)
Analgésicos Opioides/farmacología , Encéfalo/efectos de los fármacos , Nocicepción/efectos de los fármacos , Dolor Nociceptivo/prevención & control , Oxicodona/farmacología , Umbral del Dolor/efectos de los fármacos , Receptores Opioides delta/agonistas , Analgésicos Opioides/administración & dosificación , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Genotipo , Inyecciones Intraventriculares , Inyecciones Subcutáneas , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Antagonistas de Narcóticos/farmacología , Dolor Nociceptivo/genética , Dolor Nociceptivo/metabolismo , Dolor Nociceptivo/fisiopatología , Oxicodona/administración & dosificación , Fenotipo , Receptores Opioides delta/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de TiempoRESUMEN
This study reports the synthesis of a series of 2-aroylquinoline-5,8-diones (11-23) on the basis of scaffold hopping. The presence of a methoxy group at C6 assists the highly regioselective incorporation with various amines, and simplifies the structural identification process. Among the synthetic compounds, 6-dimethylamino-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (12) and 7-pyrrolidin-1-yl-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (23) exhibit remarkable anti-proliferative activity against the cancer cell lines tested with mean IC50 values of 0.14 and 0.27 µM, respectively. Compound 23 showed moderate inhibitory activity against tubulin polymerization with an IC50 value of 5.9 µM. In a western blot analysis, 23 caused induction of HSP70 and degradation of Akt, revealing that it possesses HSP90 inhibitory activity.
Asunto(s)
Antineoplásicos/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Quinolonas/farmacología , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Proteínas del Choque Térmico HSP72/biosíntesis , Humanos , Células KB , Proteínas Proto-Oncogénicas c-akt/biosíntesis , Quinolonas/síntesis química , Quinolonas/química , Relación Estructura-Actividad , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/químicaRESUMEN
Suppression of glucose reabsorption through the inhibition of sodium-dependent glucose co-transporter 2 (SGLT2) is a promising therapeutic approach for the treatment of type 2 diabetes. To investigate the effect of C6-substitution on inhibition of SGLT2 by N-indolylglucosides, a small library of 6-triazole, 6-amide, 6-urea, and 6-thiourea N-indolylglycosides were synthesized and tested. A detailed structure-activity relationship (SAR) study culminated in the identification of 6-amide derivatives 6a and 6o as potent SGLT2 inhibitors, which were further tested for inhibitory activity against SGLT1. The data obtained indicated that 6a and 6o are mildly to moderately selective for SGLT2 over SGLT1. Both compounds were also evaluated in a urinary glucose excretion test and pharmacokinetic study; 6a was found capable of inducing urinary glucose excretion in normal SD rats.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glicósidos/química , Glicósidos/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Células CHO , Cricetulus , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Glicósidos/farmacocinética , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Ratas Sprague-Dawley , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacocinética , Bibliotecas de Moléculas Pequeñas/farmacología , Transportador 2 de Sodio-Glucosa/metabolismoRESUMEN
The induction of detoxifying enzymes and antioxidant proteins by chemopreventive agents protects cells from oxidizing substances capable of damaging DNA integrity and initiating carcinogenesis. Coniferyl aldehyde, a naturally occurring substance, has been found in many foods and edible plants. We and others previously demonstrated that trans-coniferylaldehyde (t-CA) has potential antimutagenic and antioxidant properties. However, the mechanism underlying its Nrf2-mediated antioxidant effect remains largely unknown. In the present study, we demonstrated that t-CA significantly stimulated antioxidant-responsive element (ARE)-driven luciferase activity in a cell model and increased the expression of ARE-dependent detoxifying/antioxidant genes and their protein products in vitro and in vivo. The detoxifying/antioxidant genes activated by t-CA, especially heme oxygenase-1 (HO-1), were found to be involved in its cytoprotective effects against oxidative stress and cell injuries elicited by carcinogens tert-butylhydroperoxide and arecoline. Furthermore, the t-CA-induced phosphorylation and nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) played a crucial role in this ARE-mediated cellular defense. Moreover, we found that p38 MAPK and protein kinase C (PKC) signaling pathways participated in the t-CA-induced, Nrf2-mediated cytoprotective effect. Among them, p38α/MAPKAPK-2 and an atypical PKC, PK-N3, were critical for the activation of the Nrf2/HO-1 axis by t-CA. In conclusion, we demonstrated for the first time that t-CA attenuates carcinogen-induced oxidative stress by activating Nrf2 via p38α/MAPKAPK-2- and PK-N3-dependent signaling pathways. In addition, t-CA increased the level of Nrf2-mediated detoxifying/antioxidant proteins in vivo, suggesting that t-CA may have potential for use in the management of carcinogenesis and meriting further investigation.
Asunto(s)
Acroleína/análogos & derivados , Hemo-Oxigenasa 1/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Acroleína/farmacología , Animales , Ratones , Ratones Endogámicos C57BLRESUMEN
Extracellular HSP90α (eHSP90α) is a promoter of tumor development and malignant progression. Patients with malignancies, including pancreatic ductal adenocarcinoma (PDAC), have generally shown 5~10-fold increases in serum/plasma eHSP90α levels. In this study, we developed a humanized antibody HH01 to target eHSP90α and evaluated its anticancer efficacy. HH01, with novel complementarity-determining regions, exhibits high binding affinity toward HSP90α. It recognizes HSP90α epitope sites 235AEEKEDKEEE244 and 251ESEDKPEIED260, with critical amino acid residues E237, E239, D240, K241, E253, and K255. HH01 effectively suppressed eHSP90α-induced invasive and spheroid-forming activities of colorectal cancer and PDAC cell lines by blocking eHSP90α's ligation with the cell-surface receptor CD91. In mouse models, HH01 potently inhibited the tumor growth of PDAC cell grafts/xenografts promoted by endothelial-mesenchymal transition-derived cancer-associated fibroblasts while also reducing serum eHSP90α levels, reflecting its anticancer efficacy. HH01 also modulated tumor immunity by reducing M2 macrophages and reinvigorating immune T-cells. Additionally, HH01 showed low aggregation propensity, high water solubility, and a half-life time of >18 days in mouse blood. It was not cytotoxic to retinal pigmented epithelial cells and showed no obvious toxicity in mouse organs. Our data suggest that targeting eHSP90α with HH01 antibody can be a promising novel strategy for PDAC therapy.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Proteínas HSP90 de Choque Térmico , Neoplasias Pancreáticas , Humanos , Proteínas HSP90 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Animales , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Ratones , Línea Celular Tumoral , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Adenocarcinoma/patología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/metabolismo , Transición Endotelial-MesenquimatosaRESUMEN
Aurora kinase inhibitors, such as alisertib, can destabilize MYC-family oncoproteins and have demonstrated compelling antitumor efficacy. In this study, we report 6K465, a novel pyrimidine-based Aurora A inhibitor, that reduces levels of c-MYC and N-MYC oncoproteins more potently than alisertib. In an analysis of the antiproliferative effect of 6K465, the sensitivities of small cell lung cancer (SCLC) and breast cancer cell lines to 6K465 were strongly associated with the protein levels of c-MYC and/or N-MYC. We also report DBPR728, an acyl-based prodrug of 6K465 bearing fewer hydrogen-bond donors, that exhibited 10-fold improved oral bioavailability. DBPR728 induced durable tumor regression of c-MYC- and/or N-MYC-overexpressing xenografts including SCLC, triple-negative breast cancer, hepatocellular carcinoma, and medulloblastoma using a 5-on-2-off or once-a-week dosing regimen on a 21-day cycle. A single oral dose of DBPR728 at 300 mg/kg induced c-MYC reduction and cell apoptosis in the tumor xenografts for more than 7 days. The inhibitory effect of DBPR728 at a reduced dosing frequency was attributed to its uniquely high tumor/plasma ratio (3.6-fold within 7 days) and the long tumor half-life of active moiety 6K465. Furthermore, DBPR728 was found to synergize with the mTOR inhibitor everolimus to suppress c-MYC- or N-MYC-driven SCLC. Collectively, these results suggest DBPR728 has the potential to treat cancers overexpressing c-MYC and/or N-MYC.
Asunto(s)
Aurora Quinasa A , Everolimus , Proteínas Proto-Oncogénicas c-myc , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Aurora Quinasa A/antagonistas & inhibidores , Ratones , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Everolimus/farmacología , Everolimus/farmacocinética , Everolimus/administración & dosificación , Línea Celular Tumoral , Femenino , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/farmacocinética , Proliferación Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Pirimidinas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges. We hypothesize that binding a chemical compound to the MOR may elicit a comparable effect to the S196A mutation. Through high-throughput screening and structure-activity relationship studies, we identified a modulator, 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (BPRMU191), which confers agonistic properties to small-molecule morphinan antagonists, which induce G protein-dependent MOR activation. Co-application of BPRMU191 and morphinan antagonists resulted in MOR-dependent analgesia with diminished side effects, including gastrointestinal dysfunction, antinociceptive tolerance, and physical and psychological dependence. Combining BPRMU191 and morphinan antagonists could serve as a potential therapeutic strategy for severe pain with reduced adverse effects and provide an avenue for studying G protein-coupled receptor modulation.
RESUMEN
A series of bifunctional compounds have been discovered for their dual functionality as MER/AXL inhibitors and immune modulators. The furanopyrimidine scaffold, renowned for its suitability in kinase inhibitor discovery, offers at least three distinct pharmacophore access points. Insights from molecular modeling studies guided hit-to-lead optimization, which revealed that the 1,3-diketone side chain hybridized with furanopyrimidine scaffold that respectively combined amino-type substituent and 1H-pyrazol-4-yl substituent on the top and bottom of the aryl regions to produce 22 and 33, exhibiting potent antitumor activities in various syngeneic and xenograft models. More importantly, 33 demonstrated remarkable immune-modulating activity by upregulating the expression of total T-cells, cytotoxic CD8+ T-cells, and helper CD4+ T-cells in the spleen. These findings underscored the bifunctional capabilities of 33 (BPR5K230) with excellent oral bioavailability (F = 54.6%), inhibiting both MER and AXL while modulating the tumor microenvironment and highlighting its diverse applicability for further studies to advance its therapeutic potential.
Asunto(s)
Antineoplásicos , Tirosina Quinasa del Receptor Axl , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas , Proteínas Tirosina Quinasas Receptoras , Microambiente Tumoral , Tirosina Quinasa c-Mer , Animales , Microambiente Tumoral/efectos de los fármacos , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Tirosina Quinasa c-Mer/antagonistas & inhibidores , Tirosina Quinasa c-Mer/metabolismo , Ratones , Línea Celular Tumoral , Relación Estructura-Actividad , Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Femenino , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos BALB C , Proliferación Celular/efectos de los fármacosRESUMEN
Hepatitis C virus (HCV), a member of the Flaviviridae family, affects approximately 3% of the world's population and is becoming the leading cause of liver disease in the world. Therefore, the development of novel or more effective treatment strategies to treat chronic HCV infection is urgently needed. In our previous study, we identified a potential HCV NS5A inhibitor, BP008. After further systemic optimization, we discovered a more potent HCV inhibitor, DBPR110. DBPR110 reduced the reporter expression of the HCV1b replicon with a 50% effective concentration (EC(50)) and a selective index value of 3.9 ± 0.9 pM and >12,800,000, respectively. DBPR110 reduced HCV2a replicon activity with an EC(50) and a selective index value of 228.8 ± 98.4 pM and >173,130, respectively. Sequencing analyses of several individual clones derived from the DBPR110-resistant RNAs purified from cells harboring genotype 1b and 2a HCV replicons revealed that amino acid substitutions mainly within the N-terminal region (domain I) of NS5A were associated with decreased inhibitor susceptibility. P58L/T and Y93H/N in genotype 1b and T24A, P58L, and Y93H in the genotype 2a replicon were the key substitutions for resistance selection. In the 1b replicon, V153M, M202L, and M265V play a compensatory role in replication and drug resistance. Moreover, DBPR110 displayed synergistic effects with alpha interferon (IFN-α), an NS3 protease inhibitor, and an NS5B polymerase inhibitor. In summary, our results present an effective small-molecule inhibitor, DBPR110, that potentially targets HCV NS5A. DBPR110 could be part of a more effective therapeutic strategy for HCV in the future.
Asunto(s)
Antivirales/farmacología , Farmacorresistencia Viral/genética , Hepatitis C Crónica/tratamiento farmacológico , Pirrolidinas/farmacología , Tiazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sustitución de Aminoácidos , Antivirales/química , Línea Celular Tumoral , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C Crónica/virología , Humanos , Interferón-alfa/farmacología , Mutación , Unión Proteica , ARN Viral/análisis , Replicón , Análisis de Secuencia de ARN , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/genéticaRESUMEN
A series of 1-arylsulfonyl-5-(N-hydroxyacrylamide)indolines (7-15) has been developed; the compounds exhibited potent histone deacetylase (HDAC) inhibitory activities. Notably, almost all of this series exhibited better HDAC-inhibitory and antiproliferative activities than 3-(1-benzenesulfonyl-1H-indol-5-yl)-N-hydroxyacrylamide (6), as reported in a previous study. Among these compounds, 3-[1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-5-yl]-N-hydroxyacrylamide (9) showed a two- to tenfold increase in activity compared to SAHA (1) in the suppression of lipopolysaccharide-induced cytokine production. Compound 9 also caused a marked reduction in carrageenan-induced acute inflammation in a rat model. Taken together, these data indicated that 1-arylsulfonyl-5-(N-hydroxyacrylamide)indolines HDAC inhibitors exhibit potent anti-inflammatory activity.