title: Application of chemoproteomics to drug discovery: identification of a clinical candidate targeting hsp90.
abstract: A chemoproteomics-based drug discovery strategy is presented that utilizes a highly parallel screening platform, encompassing more than 1000 targets, with a focused chemical library prior to target selection. This chemoproteomics-based process enables a data-driven selection of both the biological target and chemical hit after the screen is complete. The methodology has been exemplified for the purine binding proteome (proteins utilizing ATP, NAD, FAD). Screening of an 8000 member library yielded over 1500 unique protein-ligand interactions, which included novel hits for the oncology target Hsp90. The approach, which also provides broad target selectivity information, was used to drive the identification of a potent and orally active Hsp90 inhibitor, SNX-5422, which is currently in phase 1 clinical studies.
authors.affiliation: Serenex, Inc., 323 Foster Street, Durham, NC 27701, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Fadden
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Huang
authors.forename: James M
authors.initials: JM
authors.lastname: Veal
authors.forename: Paul M
authors.initials: PM
authors.lastname: Steed
authors.forename: Amy F
authors.initials: AF
authors.lastname: Barabasz
authors.forename: Briana
authors.initials: B
authors.lastname: Foley
authors.forename: Mei
authors.initials: M
authors.lastname: Hu
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Partridge
authors.forename: John
authors.initials: J
authors.lastname: Rice
authors.forename: Anisa
authors.initials: A
authors.lastname: Scott
authors.forename: Laura G
authors.initials: LG
authors.lastname: Dubois
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Freed
authors.forename: Melanie A Rehder
authors.initials: MA
authors.lastname: Silinski
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Barta
authors.forename: Philip F
authors.initials: PF
authors.lastname: Hughes
authors.forename: Andy
authors.initials: A
authors.lastname: Ommen
authors.forename: Wei
authors.initials: W
authors.lastname: Ma
authors.forename: Emilie D
authors.initials: ED
authors.lastname: Smith
authors.forename: Angela Woodward
authors.initials: AW
authors.lastname: Spangenberg
authors.forename: Jeron
authors.initials: J
authors.lastname: Eaves
authors.forename: Gunnar J
authors.initials: GJ
authors.lastname: Hanson
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hinkley
authors.forename: Matthew
authors.initials: M
authors.lastname: Jenks
authors.forename: Meredith
authors.initials: M
authors.lastname: Lewis
authors.forename: James
authors.initials: J
authors.lastname: Otto
authors.forename: Gijsbertus J
authors.initials: GJ
authors.lastname: Pronk
authors.forename: Katleen
authors.initials: K
authors.lastname: Verleysen
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Haystead
authors.forename: Steven E
authors.initials: SE
authors.lastname: Hall
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D017321:Clinical Trials, Phase I as Topic; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D040901:Proteomics / Q000379:methods*; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013379:Substrate Specificity
chemical_list: D018841:HSP90 Heat-Shock Proteins; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate