title: Discovery of 1-(1H-Pyrazolo[4,3-c]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers.
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.
authors.affiliation: 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 States.
authors.forename: Jongwon
authors.initials: J
authors.lastname: Lim
authors.affiliation: 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 States.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Kelley
authors.affiliation: 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 States.
authors.forename: Joey L
authors.initials: JL
authors.lastname: Methot
authors.affiliation: 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 States.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: 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 States.
authors.forename: Alessia
authors.initials: A
authors.lastname: Petrocchi
authors.affiliation: 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 States.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Chen
authors.affiliation: 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 States.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Hill
authors.affiliation: 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 States.
authors.forename: Marlene C
authors.initials: MC
authors.lastname: Hinton
authors.affiliation: 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 States.
authors.forename: Alan
authors.initials: A
authors.lastname: Hruza
authors.affiliation: 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 States.
authors.forename: Joon O
authors.initials: JO
authors.lastname: Jung
authors.affiliation: 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 States.
authors.forename: John K F
authors.initials: JK
authors.lastname: Maclean
authors.affiliation: 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 States.
authors.forename: My
authors.initials: M
authors.lastname: Mansueto
authors.affiliation: 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 States.
authors.forename: George N
authors.initials: GN
authors.lastname: Naumov
authors.affiliation: 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 States.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Philippar
authors.affiliation: 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 States.
authors.forename: Shruti
authors.initials: S
authors.lastname: Raut
authors.affiliation: 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 States.
authors.forename: Peter
authors.initials: P
authors.lastname: Spacciapoli
authors.affiliation: 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 States.
authors.forename: Dongyu
authors.initials: D
authors.lastname: Sun
authors.affiliation: 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 States.
authors.forename: Phieng
authors.initials: P
authors.lastname: Siliphaivanh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C000619474:1-(3-(2-methylpyridin-4-yl)-1H-pyrazolo(4,3-c)pyridin-6-yl)-3-(1-phenylethyl)urea; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014508:Urea; D048049:Extracellular Signal-Regulated MAP Kinases