title: Natural Product Inspired N-Terminal Hsp90 Inhibitors: From Bench to Bedside?
abstract: The 90 kDa heat shock proteins (Hsp90) are responsible for the conformational maturation of nascent polypeptides and the rematuration of denatured proteins. Proteins dependent upon Hsp90 are associated with all six hallmarks of cancer. Upon Hsp90 inhibition, protein substrates are degraded via the ubiquitin-proteasome pathway. Consequentially, inhibition of Hsp90 offers a therapeutic opportunity for the treatment of cancer. Natural product inhibitors of Hsp90 have been identified in vitro, which have served as leads for the development of more efficacious inhibitors and analogs that have entered clinical trials. This review highlights the development of natural product analogs, as well as the development of clinically important inhibitors that arose from natural products.
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, KS 66045.
authors.forename: Anuj
authors.initials: A
authors.lastname: Khandelwal
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, KS 66045.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Crowley
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, KS 66045.
authors.forename: Brian S J
authors.initials: BSJ
authors.lastname: Blagg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D016227:Benzoquinones / Q000737:chemistry; D001688:Biological Products / Q000737:chemistry*; D015195:Drug Design; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic / Q000737:chemistry; D018942:Macrolides / Q000737:chemistry; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011687:Purines / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D001688:Biological Products; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; D011687:Purines; C035359:monorden; C001277:geldanamycin
keywords: Hsp90; chaperone; geldanamycin; natural product-based drug design; radicicol