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1.
Bioorg Med Chem Lett ; 18(23): 6171-4, 2008 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-18951019

RESUMEN

This paper reports a second generation MEK inhibitor. The previously reported potent and efficacious MEK inhibitor, PD-184352 (CI-1040), contains an integral hydroxamate moiety. This compound suffered from less than ideal solubility and metabolic stability. An oxadiazole moiety behaves as a bioisostere for the hydroxamate group, leading to a more metabolically stable and efficacious MEK inhibitor.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzamidas/farmacología , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Antineoplásicos/química , Benzamidas/química , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/tratamiento farmacológico , Técnicas Químicas Combinatorias , Ensayos de Selección de Medicamentos Antitumorales , Ésteres , Humanos , Ácidos Hidroxámicos/química , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Oxadiazoles/química , Relación Estructura-Actividad
2.
Bioorg Med Chem Lett ; 18(24): 6501-4, 2008 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-18952427

RESUMEN

A novel series of benzhydroxamate esters derived from their precursor anthranilic acids have been prepared and have been identified as potent MEK inhibitors. 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide, CI-1040, was the first MEK inhibitor to demonstrate in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated. Optimization of the diphenylamine core and modification of the hydroxamate side chain for cell potency, solubility, and exposure with oral delivery resulted in the discovery of the clinical candidate N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide PD 0325901.


Asunto(s)
Benzamidas/síntesis química , Difenilamina/análogos & derivados , Inhibidores Enzimáticos/síntesis química , Quinasa 1 de Quinasa de Quinasa MAP/antagonistas & inhibidores , Animales , Benzamidas/farmacología , Benzoatos/química , Línea Celular Tumoral , Química Farmacéutica/métodos , Difenilamina/síntesis química , Difenilamina/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Ácidos Hidroxámicos/química , Concentración 50 Inhibidora , Ratones , Trasplante de Neoplasias , Solubilidad , ortoaminobenzoatos/química
3.
J Med Chem ; 50(21): 5090-102, 2007 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-17880056

RESUMEN

A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.


Asunto(s)
Amidas/síntesis química , Compuestos de Anilina/síntesis química , Antineoplásicos/síntesis química , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 2/antagonistas & inhibidores , Piridonas/síntesis química , Amidas/química , Amidas/farmacología , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Benzamidas/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , MAP Quinasa Quinasa 1/química , MAP Quinasa Quinasa 2/química , Masculino , Ratones , Modelos Moleculares , Trasplante de Neoplasias , Fosforilación , Piridonas/química , Piridonas/farmacología , Ratas , Relación Estructura-Actividad
4.
Nat Struct Mol Biol ; 11(12): 1192-7, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15543157

RESUMEN

MEK1 and MEK2 are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. Approximately 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here we present the X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively. The structures reveal that MEK1 and MEK2 each have a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitor induces several conformational changes in the unphosphorylated MEK1 and MEK2 enzymes that lock them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.


Asunto(s)
Inhibidores Enzimáticos/farmacología , MAP Quinasa Quinasa 1/química , MAP Quinasa Quinasa 1/metabolismo , MAP Quinasa Quinasa 2/química , MAP Quinasa Quinasa 2/metabolismo , Sitios de Unión , Secuencia Conservada , Dimerización , Inhibidores Enzimáticos/química , Humanos , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 2/antagonistas & inhibidores , Modelos Moleculares , Estructura Molecular , Estructura Cuaternaria de Proteína , Homología Estructural de Proteína
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