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Discovery of 1-(1H-Pyrazolo[4,3-c]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers.
Lim, Jongwon; Kelley, Elizabeth H; Methot, Joey L; Zhou, Hua; Petrocchi, Alessia; Chen, Hongmin; Hill, Susan E; Hinton, Marlene C; Hruza, Alan; Jung, Joon O; Maclean, John K F; Mansueto, My; Naumov, George N; Philippar, Ulrike; Raut, Shruti; Spacciapoli, Peter; Sun, Dongyu; Siliphaivanh, Phieng.
Afiliação
  • Lim J; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Kelley EH; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Methot JL; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Zhou H; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Petrocchi A; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Chen H; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Hill SE; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Hinton MC; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Hruza A; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Jung JO; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Maclean JK; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Mansueto M; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Naumov GN; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Philippar U; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Raut S; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Spacciapoli P; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Sun D; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
  • Siliphaivanh P; Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United
J Med Chem ; 59(13): 6501-11, 2016 07 14.
Article em En | MEDLINE | ID: mdl-27329786
ABSTRACT
The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the ERK signal pathway. Acquired resistance to these agents has led to greater interest in ERK, a downstream target of the MAPK pathway. De novo design efforts of a novel scaffold derived from SCH772984 by employing hydrogen bond interactions specific for ERK in the binding pocket identified 1-(1H-pyrazolo[4,3-c]pyridin-6-yl)ureas as a viable lead series. Sequential SAR studies led to the identification of highly potent and selective ERK inhibitors with low molecular weight and high LE. Compound 21 exhibited potent target engagement and strong tumor regression in the BRAF(V600E) xenograft model.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridinas / Ureia / MAP Quinases Reguladas por Sinal Extracelular / Inibidores de Proteínas Quinases / Descoberta de Drogas / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridinas / Ureia / MAP Quinases Reguladas por Sinal Extracelular / Inibidores de Proteínas Quinases / Descoberta de Drogas / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2016 Tipo de documento: Article