title: Discovery and design of novel HSP90 inhibitors using multiple fragment-based design strategies.
abstract: The molecular chaperone HSP90 has been shown to facilitate cancer cell survival by stabilizing key proteins responsible for a malignant phenotype. We report here the results of parallel fragment-based drug design approaches in the design of novel HSP90 inhibitors. Initial aminopyrimidine leads were elaborated using high-throughput organic synthesis to yield nanomolar inhibitors of the enzyme. Second site leads were also identified which bound to HSP90 in two distinct conformations, an 'open' and 'closed' form. Intriguingly, linked fragment approaches targeting both of these conformations were successful in producing novel, micromolar inhibitors. Overall, this study shows that, with only a few fragment hits, multiple lead series can be generated for HSP90 due to the inherent flexibility of the active site. Thus, ample opportunities exist to use these lead series in the development of clinically useful HSP90 inhibitors for the treatment of cancers.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Huth
authors.forename: Chang
authors.initials: C
authors.lastname: Park
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Kunzer
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wendt
authors.forename: Xilu
authors.initials: X
authors.lastname: Wang
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Lynch
authors.forename: Jamey C
authors.initials: JC
authors.lastname: Mack
authors.forename: Kerry M
authors.initials: KM
authors.lastname: Swift
authors.forename: Russell A
authors.initials: RA
authors.lastname: Judge
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Paul L
authors.initials: PL
authors.lastname: Richardson
authors.forename: Sha
authors.initials: S
authors.lastname: Jin
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tahir
authors.forename: Edward D
authors.initials: ED
authors.lastname: Matayoshi
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Dorwin
authors.forename: Uri S
authors.initials: US
authors.lastname: Ladror
authors.forename: Jean M
authors.initials: JM
authors.lastname: Severin
authors.forename: Karl A
authors.initials: KA
authors.lastname: Walter
authors.forename: Diane M
authors.initials: DM
authors.lastname: Bartley
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hajduk
mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D000631:Aminopyridines; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D010446:Peptide Fragments