ABSTRACT
Autophagy is postulated to be required by cancer cells to survive periods of metabolic and/or hypoxic stress. ATG7 is the E1 enzyme that is required for activation of Ubl conjugation pathways involved in autophagosome formation. This article describes the design and optimization of pyrazolopyrimidine sulfamate compounds as potent and selective inhibitors of ATG7. Cellular levels of the autophagy markers, LC3B and NBR1, are regulated following treatment with these compounds.
Subject(s)
Autophagy-Related Protein 7/antagonists & inhibitors , Drug Discovery , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Sulfonic Acids/pharmacology , Autophagy/drug effects , Autophagy-Related Protein 7/metabolism , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship , Sulfonic Acids/chemical synthesis , Sulfonic Acids/chemistryABSTRACT
Investigations of a biaryl ether scaffold identified tetrahydronaphthalene Raf inhibitors with good in vivo activity; however these compounds had affinity toward the hERG potassium channel. Herein we describe our work to eliminate this hERG activity via alteration of the substituents on the benzoic amide functionality. The resulting compounds have improved selectivity against the hERG channel, good pharmacokinetic properties and potently inhibit the Raf pathway in vivo.
Subject(s)
Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Tetrahydronaphthalenes/chemistry , Animals , Cell Line, Tumor , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Inhibitory Concentration 50 , Male , Mice , Mutagenesis , Neoplasms/drug therapy , Neoplasms/pathology , Protein Binding , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tetrahydronaphthalenes/pharmacokinetics , Tetrahydronaphthalenes/therapeutic use , Transplantation, HeterologousABSTRACT
Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.
Subject(s)
Antineoplastic Agents/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Tetrahydronaphthalenes/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Availability , Crystallography, X-Ray , Drug Design , Melanoma, Experimental/drug therapy , Melanoma, Experimental/enzymology , Melanoma, Experimental/pathology , Mice , Mice, Nude , Models, Molecular , Mutation , Proto-Oncogene Proteins B-raf/genetics , Stereoisomerism , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
A novel series of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R) is reported. Members of this series have been identified, which exhibit sub-micromolar binding affinity for the MC4-R, functional potency <100nM, and good oral exposure in rat. Antagonists of the MC4-R are potentially useful in the therapeutic treatment of involuntary weight loss due to advanced age or disease (e.g. cancer or AIDS), an area of large, unmet medical need.
Subject(s)
Body Weight/drug effects , Imidazoles/chemical synthesis , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Animals , Binding Sites , Body Weight/physiology , Cells, Cultured , Imidazoles/pharmacology , Rats , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity RelationshipABSTRACT
Angiotensin-converting enzyme-related carboxypeptidase (ACE2) is a recently identified zinc metalloprotease with carboxypeptidase activity that was identified using our genomics platform. We implemented a rational design approach to identify potent and selective ACE2 inhibitors. To this end, picomolar inhibitors of ACE2 were designed and synthesized.
