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1.
Immunol Cell Biol ; 96(1): 81-99, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29359407

RESUMEN

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is essential for immune responses triggered by antigen receptors but the contribution of its paracaspase activity is not fully understood. Here, we studied how MALT1 proteolytic function regulates T-cell activation and fate after engagement of the T-cell receptor pathway. We show that MLT-827, a potent and selective MALT1 paracaspase inhibitor, does not prevent the initial phase of T-cell activation, in contrast to the pan-protein kinase C inhibitor AEB071. However, MLT-827 strongly impacted cell expansion after activation. We demonstrate this is the consequence of profound inhibition of IL-2 production as well as reduced expression of the IL-2 receptor alpha subunit (CD25), resulting from defective canonical NF-κB activation and accelerated mRNA turnover mechanisms. Accordingly, MLT-827 revealed a unique transcriptional fingerprint of MALT1 protease activity, providing evidence for broad control of T-cell signaling pathways. Altogether, this first report with a potent and selective inhibitor elucidates how MALT1 paracaspase activity integrates several T-cell activation pathways and indirectly controls gamma-chain receptor dependent survival, to impact on T-cell expansion.


Asunto(s)
Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , FN-kappa B/metabolismo , Linfocitos T/inmunología , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Regulación de la Expresión Génica , Humanos , Inmunomodulación , Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Activación de Linfocitos , Proteolisis , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal
2.
Angew Chem Int Ed Engl ; 54(48): 14575-9, 2015 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-26457482

RESUMEN

Targeting drugs to their desired site of action can increase their safety and efficacy. Bisphosphonates are prototypical examples of drugs targeted to bone. However, bisphosphonate bone affinity is often considered too strong and cannot be significantly modulated without losing activity on the enzymatic target, farnesyl pyrophosphate synthase (FPPS). Furthermore, bisphosphonate bone affinity comes at the expense of very low and variable oral bioavailability. FPPS inhibitors were developed with a monophosphonate as a bone-affinity tag that confers moderate affinity to bone, which can furthermore be tuned to the desired level, and the relationship between structure and bone affinity was evaluated by using an NMR-based bone-binding assay. The concept of targeting drugs to bone with moderate affinity, while retaining oral bioavailability, has broad application to a variety of other bone-targeted drugs.


Asunto(s)
Huesos/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Administración Oral , Disponibilidad Biológica , Huesos/enzimología , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Geraniltranstransferasa/antagonistas & inhibidores , Humanos
3.
Bioorg Med Chem Lett ; 24(9): 2110-4, 2014 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-24704029

RESUMEN

Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53-MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein-protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Imidazoles/química , Imidazoles/farmacología , Mapas de Interacción de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores
4.
Blood ; 112(13): 5161-70, 2008 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-18820131

RESUMEN

An attractive target for therapeutic intervention is constitutively activated, mutant FLT3, which is expressed in a subpopulation of patients with acute myelocyic leukemia (AML) and is generally a poor prognostic indicator in patients under the age of 65 years. PKC412 is one of several mutant FLT3 inhibitors that is undergoing clinical testing, and which is currently in late-stage clinical trials. However, the discovery of drug-resistant leukemic blast cells in PKC412-treated patients with AML has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to override drug resistance. Here, we report the potent and selective antiproliferative effects of the novel mutant FLT3 inhibitor NVP-AST487 on primary patient cells and cell lines expressing FLT3-ITD or FLT3 kinase domain point mutants. NVP-AST487, which selectively targets mutant FLT3 protein kinase activity, is also shown to override PKC412 resistance in vitro, and has significant antileukemic activity in an in vivo model of FLT3-ITD(+) leukemia. Finally, the combination of NVP-AST487 with standard chemotherapeutic agents leads to enhanced inhibition of proliferation of mutant FLT3-expressing cells. Thus, we present a novel class of FLT3 inhibitors that displays high selectivity and potency toward FLT3 as a molecular target, and which could potentially be used to override drug resistance in AML.


Asunto(s)
Antineoplásicos/farmacología , Carbanilidas/farmacología , Resistencia a Antineoplásicos , Inhibidores de Proteínas Quinasas/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular , Leucemia Mieloide Aguda/tratamiento farmacológico , Ratones , Proteínas Mutantes/antagonistas & inhibidores , Proteína Quinasa C/antagonistas & inhibidores , Estaurosporina/análogos & derivados
5.
J Med Chem ; 63(23): 14576-14593, 2020 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-33252239

RESUMEN

MALT1 plays a central role in immune cell activation by transducing NF-κB signaling, and its proteolytic activity represents a key node for therapeutic intervention. Two cycles of scaffold morphing of a high-throughput biochemical screening hit resulted in the discovery of MLT-231, which enabled the successful pharmacological validation of MALT1 allosteric inhibition in preclinical models of humoral immune responses and B-cell lymphomas. Herein, we report the structural activity relationships (SARs) and analysis of the physicochemical properties of a pyrazolopyrimidine-derived compound series. In human T-cells and B-cell lymphoma lines, MLT-231 potently and selectively inhibits the proteolytic activity of MALT1 in NF-κB-dependent assays. Both in vitro and in vivo profiling of MLT-231 support further optimization of this in vivo tool compound toward preclinical characterization.


Asunto(s)
Inhibidores de Caspasas/uso terapéutico , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Urea/análogos & derivados , Urea/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inhibidores de Caspasas/síntesis química , Inhibidores de Caspasas/farmacología , Descubrimiento de Drogas , Femenino , Humanos , Inmunidad Humoral/efectos de los fármacos , Masculino , Ratones Endogámicos BALB C , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/farmacología , Pirazoles/uso terapéutico , Pirimidinas/síntesis química , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas Sprague-Dawley , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Urea/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Am J Pathol ; 173(1): 265-77, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18535184

RESUMEN

Although vascular remodeling is a hallmark of many chronic inflammatory disorders, antivascular strategies to treat these conditions have received little attention to date. We investigated the effects of a newly identified vascular endothelial growth factor (VEGF) receptor tyrosine-kinase inhibitor, NVP-BAW2881, on endothelial cell function in vitro and its anti-inflammatory activity in different animal models. NVP-BAW2881 inhibited proliferation, migration, and tube formation by human umbilical vein endothelial cells and lymphatic endothelial cells in vitro. In a transgenic mouse model of psoriasis, NVP-BAW2881 reduced the number of blood and lymphatic vessels and infiltrating leukocytes in the skin, and normalized the epidermal architecture. NVP-BAW2881 also displayed strong anti-inflammatory effects in models of acute inflammation; pretreatment with topical NVP-BAW2881 significantly inhibited VEGF-A-induced vascular permeability in the skin of pigs and mice. Furthermore, topical application of NVP-BAW2881 reduced the inflammatory response elicited in pig skin by UV-B irradiation or by contact hypersensitivity reactions. These results demonstrate for the first time that VEGF receptor tyrosine-kinase inhibitors might be used to treat patients with inflammatory skin disorders such as psoriasis.


Asunto(s)
Antiinflamatorios/farmacología , Inflamación/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Enfermedades de la Piel/tratamiento farmacológico , Piel/efectos de los fármacos , Animales , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Enfermedad Crónica , Femenino , Humanos , Linfangiogénesis/efectos de los fármacos , Ratones , Ratones Transgénicos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/efectos de los fármacos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/efectos de los fármacos , Piel/irrigación sanguínea , Piel/efectos de la radiación , Sus scrofa
7.
J Med Chem ; 49(15): 4451-4, 2006 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-16854049

RESUMEN

FLT3 kinase inhibitors are currently under investigation as a new treatment for acute myeloid leukemia. We report here a molecular concept invoking interactions between an aromatic ring and the side chains of Phe691 and Cys828, two residues of the ATP pocket, to obtain potent and specific inhibitors of this kinase. The hypothesis has been validated by the successful design of a new inhibitor prototype showing promising antiproliferative activity in cellular assays.


Asunto(s)
Antineoplásicos/síntesis química , Cisteína/química , Fenilalanina/química , Tiazoles/síntesis química , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/química , Enfermedad Aguda , Adenosina Trifosfato/química , Antineoplásicos/química , Sitios de Unión , Línea Celular Tumoral , Humanos , Leucemia Mieloide , Modelos Moleculares , Mutación , Estructura Terciaria de Proteína , Tiazoles/química , Tiazoles/farmacología , Tirosina Quinasa 3 Similar a fms/genética
8.
J Med Chem ; 59(1): 132-46, 2016 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-26629594

RESUMEN

This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides as a new class of potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds of this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis in a chamber model and rodent tumor models at daily doses of less than 3 mg/kg by targeting the tumor vasculature as demonstrated by ELISA for TIE-2 in lysates or by immunohistochemical analysis. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.


Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/farmacocinética , Animales , Células CHO , Proliferación Celular/efectos de los fármacos , Cricetinae , Cricetulus , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Melanoma Experimental/tratamiento farmacológico , Ratones , Modelos Moleculares , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Fosforilación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Factor A de Crecimiento Endotelial Vascular/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Biochim Biophys Acta ; 1697(1-2): 17-27, 2004 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-15023347

RESUMEN

Initial studies with angiogenesis inhibitors showed little clinical benefit. However, recently reported clinical studies in colorectal cancer have shown that bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with cytotoxic therapy has positive effects on patient survival. Furthermore, the VEGF receptor kinase (VEGF-R) tyrosine kinase inhibitor, vatalanib, has also shown encouraging results in colorectal cancer, with molecular resonance imaging providing evidence that the anti-tumor efficacy was indeed the result of anti-angiogenic activity. Both of these agents are progressing in phase III trials. This proof of concept has stimulated the desire for second-generation VEGF-R inhibitors having an improved profile. Structural biology insight regarding the binding mode of protein kinase inhibitors is valuable for the design of molecules possessing superior selectivity, efficacy and tolerability. Towards this goal, we have developed a new series of VEGF-R2 kinase inhibitors, based upon an anthranilic acid amide scaffold. An X-ray crystal structure of a representative compound, AAL993 (ZK260253), in complex with the catalytic domain of diphosphorylated VEGF-R2 has revealed that this molecule binds to an inactive conformation of the protein. This binding mode, similar to that observed for the anti-leukemia drug, imatinib in complex with c-Abl kinase, may be responsible for the high selectivity of AAL993 and provides valuable insight for the design of further compounds.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Inhibidores Enzimáticos/farmacología , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/metabolismo , Animales , Ensayos Clínicos como Asunto , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Humanos , Modelos Moleculares , Neovascularización Patológica/tratamiento farmacológico , Unión Proteica , Receptores de Factores de Crecimiento Endotelial Vascular/química
10.
ChemMedChem ; 10(11): 1884-91, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26381451

RESUMEN

Farnesyl pyrophosphate synthase (FPPS) is an established target for the treatment of bone diseases, but also shows promise as an anticancer and anti-infective drug target. Currently available anti-FPPS drugs are active-site-directed bisphosphonate inhibitors, the peculiar pharmacological profile of which is inadequate for therapeutic indications beyond bone diseases. The recent discovery of an allosteric binding site has paved the way toward the development of novel non-bisphosphonate FPPS inhibitors with broader therapeutic potential, notably as immunomodulators in oncology. Herein we report the discovery, by an integrated lead finding approach, of two new chemical classes of allosteric FPPS inhibitors that belong to the salicylic acid and quinoline chemotypes. We present their synthesis, biochemical and cellular activities, structure-activity relationships, and provide X-ray structures of several representative FPPS complexes. These novel allosteric FPPS inhibitors are devoid of any affinity for bone mineral and could serve as leads to evaluate their potential in none-bone diseases.


Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Geraniltranstransferasa/antagonistas & inhibidores , Quinolinas/farmacología , Ácido Salicílico/farmacología , Regulación Alostérica/efectos de los fármacos , Sitio Alostérico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Geraniltranstransferasa/metabolismo , Humanos , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Ácido Salicílico/síntesis química , Ácido Salicílico/química , Relación Estructura-Actividad
11.
J Med Chem ; 45(26): 5687-93, 2002 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-12477352

RESUMEN

Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors have been prepared and evaluated as angiogenesis inhibitors. 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3-isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their physicochemical properties, these anthranilamides readily penetrate cells and are absorbed following once daily oral administration to mice. Both 5 and 7 potently inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7 mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both the growth of the primary tumor as well as the formation of spontaneous peripheral metastases. The anthranilamides 5 and 7 represent a new structural class of VEGFR kinase inhibitors, which possess potent antiangiogenic and antitumor properties.


Asunto(s)
Antineoplásicos/síntesis química , Benzamidas/síntesis química , Inhibidores Enzimáticos/síntesis química , Isoquinolinas/síntesis química , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , ortoaminobenzoatos/síntesis química , Administración Oral , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Benzamidas/química , Benzamidas/farmacología , Células CHO , Cricetinae , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Isoquinolinas/química , Isoquinolinas/farmacología , Metástasis Linfática , Melanoma/tratamiento farmacológico , Melanoma/patología , Ratones , Fosforilación , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacología
12.
Eur J Med Chem ; 39(1): 11-26, 2004 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-14987830

RESUMEN

A pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase and a putative binding mode of 4-anilinoquinazoline suggest that a salicylic acid function could serve as the pharmacophore replacement of a pyrimidine ring. Superpositions by CAMM of salicylanilides with the potent EGFR tyrosine kinase inhibitor 4-[(3'-chlorophenyl)amino]-6,7-dimethoxyquinazoline showed that salicylanilides should act as tyrosine kinase inhibitors. A series of salicylanilides was synthesized and their inhibitory activity against tyrosine kinases determined. Some of them indeed proved to be potent and selective EGFR tyrosine kinase inhibitors. The most potent ones being 28, 16, 20, 6, and 15, with IC(50) in the 23-71 nM range.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Receptores ErbB/antagonistas & inhibidores , Salicilanilidas/farmacología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Estructura Molecular , Salicilanilidas/síntesis química , Relación Estructura-Actividad
13.
Int J Oncol ; 45(6): 2267-77, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25340839

RESUMEN

Leiomyosarcomas remain challenging tumors to manage and novel therapy strategies besides radiation and conventional chemotherapy are needed. Targeting angiogenesis by inhibition of vascular endothelial growth factor (VEGF) receptor tyrosine kinases (RTKs) of the tumor vasculature with small molecules is a promising new therapy. It has been shown recently that these receptors are not only expressed on tumor endothelium but also on tumor cells themselves. Thus, we investigated the expression of members of the VEGF receptor (VEGFR) family and corresponding growth factors in leiomyosarcoma tissue specimens and in the leiomyosarcoma cell lines SK-LMS-1 and SK-UT-1. We evaluated the influence of the VEGFR inhibitor PTK787/ZK222584 (PTK787) on cell growth, migration, apoptosis and phosphorylation of intracellular signalling molecules. In human leiomyosarcoma tissue specimens VEGFR­1/-2 and platelet-derived growth factor receptor (PDGFR-ß) were strongly expressed. Both leiomyosarcoma cell lines expressed VEGFR­1/-3 and PDGFR-ß but VEGFR-2 protein expression was positive only in SK-UT-1. SK-LMS-1 and SK-UT-1 cells secreted high and low amounts of VEGF-A, respectively, whereas PDGF-BB secretion was similar in both cell lines. Application of PTK787 led to partial inhibition of PDGF-BB-activated AKT/p90RSK and ERK1/2 signalling pathways. In contrast, protein phosphorylation was not affected by PTK787 in VEGF-A-treated cells. PTK787 turned out to inhibit cell migration even though no effects were observed upon stimulation with VEGF-A or PDGF-BB. In line, cell growth in leiomyosarcoma cell lines remained unchanged upon PTK787 treatment alone and with subsequent VEGF-A- or PDGF-BB-stimulation. However, VEGF-A, but not PDGF-BB-treated cells showed increased cell death upon PTK787 treatment. VEGFR family members are expressed in leiomyosarcomas in vivo and in vitro. Upon receptor stimulation, PTK787 is able to inhibit subsequent phosphorylation events and influences cell survival but not metabolic activity and migration. Thus, the inhibitor is possibly an additional option in the treatment of leiomyosarcomas.


Asunto(s)
Leiomiosarcoma/tratamiento farmacológico , Neovascularización Patológica/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Receptor 2 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Receptor 3 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Inhibidores de la Angiogénesis/administración & dosificación , Becaplermina , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Neovascularización Patológica/tratamiento farmacológico , Ftalazinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-sis/administración & dosificación , Proteínas Proto-Oncogénicas c-sis/biosíntesis , Piridinas/administración & dosificación , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 3 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
14.
Genes Cancer ; 1(10): 1021-32, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21779428

RESUMEN

Constitutively activated mutant FLT3 has emerged as a promising target for therapy for the subpopulation of acute myeloid leukemia (AML) patients who harbor it. The small molecule inhibitor, PKC412, targets mutant FLT3 and is currently in late-stage clinical trials. However, the identification of PKC412-resistant leukemic blast cells in the bone marrow of AML patients has propelled the development of novel and structurally distinct FLT3 inhibitors that have the potential to override drug resistance and more efficiently prevent disease progression or recurrence. Here, we present the novel first-generation "type II" FLT3 inhibitors, AFG206, AFG210, and AHL196, and the second-generation "type II" derivatives and AST487 analogs, AUZ454 and ATH686. All agents potently and selectively target mutant FLT3 protein kinase activity and inhibit the proliferation of cells harboring FLT3 mutants via induction of apoptosis and cell cycle inhibition. Cross-resistance between "type I" inhibitors, PKC412 and AAE871, was demonstrated. While cross-resistance was also observed between "type I" and first-generation "type II" FLT3 inhibitors, the high potency of the second-generation "type II" inhibitors was sufficient to potently kill "type I" inhibitor-resistant mutant FLT3-expressing cells. The increased potency observed for the second-generation "type II" inhibitors was observed to be due to an improved interaction with the ATP pocket of FLT3, specifically associated with introduction of a piperazine moiety and placement of an amino group in position 2 of the pyrimidine ring. Thus, we present 2 structurally novel classes of FLT3 inhibitors characterized by high selectivity and potency toward mutant FLT3 as a molecular target. In addition, presentation of the antileukemic effects of "type II" inhibitors, such as AUZ454 and ATH686, highlights a new class of highly potent FLT3 inhibitors able to override drug resistance that less potent "type I" inhibitors and "type II" first-generation FLT3 inhibitors cannot.

15.
Bioorg Med Chem Lett ; 13(18): 2967-71, 2003 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-12941313

RESUMEN

The vascular endothelial growth factor (VEGF) tyrosine kinase receptors KDR and Flt-1 are targets of current interest in anticancer drug research. PTK787/ZK222584 is a potent inhibitor of these enzymes in clinical evaluation as an antiangiogenic agent. The development of a hypothesis concerning the bioactive conformation of this compound has led to the discovery of a new class of potent inhibitors of KDR and Flt-1, the anthranilamides. This could be achieved with a limited experimental effort, which only involved the testing of one archive compound and the synthesis and testing of one appropriate analogue.


Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/farmacología , Bases de Datos Factuales , Piridinas , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Conformación Molecular , Ftalazinas , Relación Estructura-Actividad , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , ortoaminobenzoatos/síntesis química , ortoaminobenzoatos/farmacología
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