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1.
Mol Carcinog ; 60(11): 734-745, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34347914

RESUMEN

The Cancer Genome Atlas (TCGA) of a pancreatic cancer cohort identified high MST1R (RON tyrosine kinase receptor) expression correlated with poor prognosis in human pancreatic cancer. RON expression is null/minimal in normal pancreas but elevates from pan-in lesions through invasive carcinomas. We report using multiple approaches RON directly regulates HIF-1α, a critical driver of genes involved in cancer cell invasion and metastasis. RON and HIF-1α are highly co-expressed in the 101 human PDAC tumors analyzed and RON expression correlated with HIF-1α expression in a subset of PDAC cell lines. knockdown of RON expression in RON positive cells blocked HIF-1α expression, whereas ectopic RON expression in RON null cells induced HIF-1α expression suggesting the direct regulation of HIF-1α by RON kinase receptor. RON regulates HIF-1α through an unreported transcriptional mechanism involving PI3 kinase-mediated AKT phosphorylation and Sp1-dependent HIF-1α promoter activity leading to increased HIF-1α mRNA expression. RON/HIF-1α modulation altered the invasive behavior of PDAC cells. A small-molecule RON kinase inhibitor decreased RON ligand, MSP-induced HIF-1α expression, and invasion of PDAC cells. Immunohistochemical analysis on RON knockdown orthotopic PDAC tumor xenograft confirmed that RON inhibition significantly blocked HIF-1α expression. RON/HIF-1α co-expression also exists in triple-negative breast cancer cells, a tumor type that also lacks molecular therapeutic targets. This is the first report describing RON/HIF-1α axis in any tumor type and is a potential novel therapeutic target.


Asunto(s)
Carcinoma Ductal Pancreático/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias Pancreáticas/patología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Regulación hacia Arriba , Animales , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Movimiento Celular , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Invasividad Neoplásica , Trasplante de Neoplasias , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Regiones Promotoras Genéticas , Proteínas Tirosina Quinasas Receptoras/genética , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Bibliotecas de Moléculas Pequeñas/farmacología , Regulación hacia Arriba/efectos de los fármacos
4.
Bioorg Med Chem Lett ; 25(17): 3706-10, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-26112445
5.
J Bioinform Comput Biol ; 20(3): 2250015, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35880255

RESUMEN

Recepteur d'Origine Nantais known as RON is a member of the receptor tyrosine kinase (RTK) superfamily which has recently gained increasing attention as cancer target for therapeutic intervention. The aim of this work was to perform an alignment-independent three-dimensional quantitative structure-activity relationship (3D QSAR) study for a series of RON inhibitors. A 3D QSAR model based on GRid-INdependent Descriptors (GRIND) methodology was generated using a set of 19 compounds with RON inhibitory activities. The generated 3D QSAR model revealed the main structural features important in the potency of RON inhibitors. The results obtained from the presented study can be used in lead optimization projects for designing of novel compounds where inhibition of RON is needed.


Asunto(s)
Relación Estructura-Actividad Cuantitativa , Proteínas Tirosina Quinasas Receptoras , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/metabolismo
6.
Mol Inform ; 41(1): e2000181, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-33274845

RESUMEN

BACKGROUND: RON (Recepteur d'Origine Nantais) receptor tyrosine kinase is a promising target for anti-cancer therapeutics. The aim of this study was to identify new RON inhibitors using virtual screening methods. METHODS: To this end, a ligand-based virtual screening approach was employed for screening of ZINC database on the homology model of RON receptor. All the selected hits were inspected in terms of drug-likeness, ADME properties, and toxicity profiles. Ligand-based similarity searches along with further filtering criteria led to the identification of two compounds, TKI1 and TKI2 that were evaluated using in vitro cell-based RON inhibition assays. RESULTS: The results showed that TKI1 and TKI2 could reduce phosphorylation of RON. Both compounds showed inhibitory activity of the downstream mTOR pathway with no apparent effects on other signaling mediators in a dose-dependent manner. CONCLUSION: These compounds can provide a basis for developing novel anti-RON inhibitors applicable to cancer therapy using medicinal chemistry-oriented optimization strategies.


Asunto(s)
Proteínas Tirosina Quinasas Receptoras , Transducción de Señal , Ligandos
8.
Bioorg Med Chem Lett ; 20(9): 2745-9, 2010 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-20363625

RESUMEN

A novel series of N-(3-fluoro-4-(2-substituted-thieno[3,2-b]pyridin-7-yloxy)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamides targeting RON receptor tyrosine kinase was designed and synthesized. SAR study of the series allowed us to identify compounds possessing either inhibitory activity of RON kinase enzyme in the low nanomolar range with low residual activity against the closely related c-Met or potent dual inhibitory activity against RON and c-Met, with no significant activity against VEGFR2 in both cases.


Asunto(s)
Antineoplásicos/química , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Humanos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacocinética , Ratas , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad
9.
Bioorg Med Chem Lett ; 19(3): 644-9, 2009 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-19114304

RESUMEN

Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.


Asunto(s)
Benzamidas/farmacología , Inhibidores Enzimáticos/farmacología , Pirimidinas/farmacología , Animales , Antineoplásicos/farmacología , Benzamidas/síntesis química , Línea Celular Tumoral , Proliferación Celular , Química Farmacéutica/métodos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores de Histona Desacetilasas , Humanos , Concentración 50 Inhibidora , Ratones , Trasplante de Neoplasias , Pirimidinas/síntesis química , Relación Estructura-Actividad
10.
Bioorg Med Chem Lett ; 19(5): 1323-8, 2009 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-19211249

RESUMEN

A series of N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.


Asunto(s)
Amidas/química , Imidazolidinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/administración & dosificación , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Amidas/farmacología , Animales , Línea Celular Tumoral , Células HCT116 , Humanos , Imidazolidinas/farmacología , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
11.
Bioorg Med Chem Lett ; 19(23): 6552-6, 2009 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-19854051

RESUMEN

A series of N-(4-(6,7-disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Estereoisomerismo , Relación Estructura-Actividad
12.
Bioorg Med Chem Lett ; 19(24): 6836-9, 2009 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-19896842
13.
Artículo en Inglés | MEDLINE | ID: mdl-30863365

RESUMEN

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON) signaling axis is active in MPM. Targeting this pathway with a small molecule inhibitor, LCRF-0004, resulted in decreased proliferation with a concomitant increase in apoptosis. Cell cycle progression was also affected. Recombinant MST1 treatment was unable to overcome the effect of LCRF-0004 in terms of either proliferation or apoptosis. Subsequently, the effect of an additional small molecular inhibitor, BMS-777607 (which targets MST1R (RON), MET, Tyro3, and Axl) also resulted in a decreased proliferative capacity of MPM cells. In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis. Additionally, elevated expression levels of MST1 also correlated with better survival. This study also determined the efficacy of LCRF-0004 and BMS-777607 in xenograft MPM models. Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy in vitro, however BMS-777607 was far superior to LCRF-0004. The in vivo and in vitro data generated by this study indicates that a multi-TKI, targeting the MST1R/MET/TAM signaling pathways, may provide a more effective therapeutic strategy for the treatment of MPM as opposed to targeting MST1R alone.

14.
Bioorg Med Chem Lett ; 18(4): 1502-6, 2008 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-18207391

RESUMEN

The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs is described. Some of these compounds were shown to inhibit HDAC1 with IC(50) values below the micromolar range, induce hyperacetylation of histones, upregulate expression of the tumor suppressor p21(WAF1/Cip1), and inhibit proliferation of human cancer cells. In addition, certain compounds of this class were active in several human tumor xenograft models in vivo.


Asunto(s)
Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Compuestos de Anilina/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Benzamidas/química , Mama/citología , Mama/efectos de los fármacos , Línea Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidores Enzimáticos/química , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células HCT116 , Histona Desacetilasa 1 , Humanos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacología , Relación Estructura-Actividad
15.
Bioorg Med Chem Lett ; 18(3): 1067-71, 2008 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-18160287

RESUMEN

Inhibition of histone deacetylases (HDAC) is emerging as a new strategy in human cancer therapy. The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides is presented herein. From the different series bearing a six-membered heteroaromatic ring studied, the s-triazine series showed the best HDAC1 enzyme and in vitro anti-proliferative activities with IC(50) values below micromolar range. Some of these compounds can also significantly reduce tumor growth in human tumor xenograft models in mice.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Pirimidinas/farmacología , Triazinas/síntesis química , Triazinas/farmacología , Animales , Antineoplásicos/química , Benzamidas/química , Modelos Animales de Enfermedad , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Ratones , Relación Estructura-Actividad , Triazinas/química
16.
Bioorg Med Chem Lett ; 17(24): 6729-33, 2007 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-17977726

RESUMEN

A variety of N-(2-amino-phenyl)-4-(heteroarylmethyl)-benzamides were designed and synthesized. These compounds were shown to inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induced hyperacetylation of histones, induced the expression of the tumor suppressor protein p21(WAF1/Cip1), and inhibited cellular proliferation. Certain compounds of this class also showed in vivo activity in various human tumor xenograft models in mice.


Asunto(s)
Benzamidas/química , Benzamidas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Aminación , Animales , Sitios de Unión , Línea Celular , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Metilación , Ratones , Modelos Moleculares , Estructura Molecular , Niacina/farmacología , Relación Estructura-Actividad , Urea/química , Vasodilatación/efectos de los fármacos , ortoaminobenzoatos/química
17.
Int J Med Chem ; 2012: 412614, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-25954527

RESUMEN

A novel series of N-(3-(6-substituted-aminopyridin-3-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting TrkA receptor tyrosine kinase was identified. SAR study of the series allowed us to design and synthesize compounds possessing inhibitory activity of TrkA kinase enzyme in the low nanomolar range with low residual activity against c-Met and with no significant activity against VEGFR2.

18.
J Med Chem ; 51(14): 4072-5, 2008 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-18570366

RESUMEN

The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.


Asunto(s)
Benzamidas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Pirimidinas/farmacología , Administración Oral , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Perros , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Masculino , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
19.
Bioorg Med Chem Lett ; 16(15): 4048-52, 2006 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-16713259

RESUMEN

Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. Novel 2-aminophenyl benzamides and acrylamides, that can inhibit human HDAC enzymes and induce hyperacetylation of histones in human cancer cells, have been designed and synthesized. These compounds selectively inhibit proliferation and cause cell cycle arrest in various human cancer cells but not in normal cells. The growth inhibition of 2-aminophenyl benzamides and acrylamides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. Compounds of this class can significantly reduce tumor growth in human tumor xenograft models.


Asunto(s)
Acrilamidas/farmacología , Benzamidas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Acrilamidas/química , Benzamidas/química , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Humanos , Relación Estructura-Actividad
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