Novobiocin Analogues That Inhibit the MAPK Pathway

• Published in: Journal of medicinal chemistry Vol. 59; no. 3; pp. 925 - 933
• Main Authors: Hall, Jessica A, Seedarala, Sahithi, Zhao, Huiping, Garg, Gaurav, Ghosh, Suman, Blagg, Brian S. J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.02.2016; Amer Chemical Soc
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Cells, Cultured; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Life Sciences & Biomedicine; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Models, Molecular; Molecular Structure; Novobiocin - analogs & derivatives; Novobiocin - chemistry; Novobiocin - pharmacology; Pharmacology & Pharmacy; Science & Technology; Signal Transduction - drug effects; Structure-Activity Relationship; HSP90 INHIBITORS; MANIFEST ANTIPROLIFERATIVE ACTIVITY; CHIP; RAF; BIOLOGICAL EVALUATION; PROTEIN 90 INHIBITORS; CANCER; DERIVATIVES; KINASES; STRATEGIES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01354

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.