title: Novobiocin Analogues That Inhibit the MAPK Pathway.
abstract: Heat shock protein 90 (Hsp90) inhibition by modulation of its N- or C-terminal binding site has become an attractive strategy for the development of anticancer chemotherapeutics. The first Hsp90 C-terminus inhibitor, novobiocin, manifested a relatively high IC50 value of ∼700 μM. Therefore, investigation of the novobiocin scaffold has led to analogues with improved antiproliferative activity (nanomolar concentrations) against several cancer cell lines. During these studies, novobiocin analogues that do not inhibit Hsp90 were identified; however, these analogues demonstrated potent antiproliferative activity. Compound 2, a novobiocin analogue, was identified as a MAPK pathway signaling disruptor that lacked Hsp90 inhibitory activity. In addition, structural modifications of compound 2 were identified that segregated Hsp90 inhibition from MAPK signaling disruption. These studies indicate that compound 2 represents a novel scaffold for disruption of MAPK pathway signaling and may serve as a useful structure for the generation of new anticancer agents.
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas , 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, Kansas 66045, United States.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Hall
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas , 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, Kansas 66045, United States.
authors.forename: Sahithi
authors.initials: S
authors.lastname: Seedarala
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas , 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, Kansas 66045, United States.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas , 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, Kansas 66045, United States.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Garg
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas , 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, Kansas 66045, United States.
authors.forename: Suman
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas , 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, Kansas 66045, United States.
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009675:Novobiocin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D009675:Novobiocin; D020928:Mitogen-Activated Protein Kinases