title: Ras oncoprotein inhibitors: the discovery of potent, ras nucleotide exchange inhibitors and the structural determination of a drug-protein complex.
abstract: The nucleotide exchange process is one of the key activation steps regulating the ras protein. This report describes the development of potent, non-nucleotide, small organic inhibitors of the ras nucleotide exchange process. These inhibitors bind to the ras protein in a previously unidentified binding pocket, without displacing bound nucleotide. This report also describes the development and use of mass spectrometry, NMR spectroscopy and molecular modeling techniques to elucidate the structure of a drug-protein complex, and aid in designing new ras inhibitor targets.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Taveras
authors.forename: S W
authors.initials: SW
authors.lastname: Remiszewski
authors.forename: R J
authors.initials: RJ
authors.lastname: Doll
authors.forename: D
authors.initials: D
authors.lastname: Cesarz
authors.forename: E C
authors.initials: EC
authors.lastname: Huang
authors.forename: P
authors.initials: P
authors.lastname: Kirschmeier
authors.forename: B N
authors.initials: BN
authors.lastname: Pramanik
authors.forename: M E
authors.initials: ME
authors.lastname: Snow
authors.forename: Y S
authors.initials: YS
authors.lastname: Wang
authors.forename: J D
authors.initials: JD
authors.lastname: del Rosario
authors.forename: B
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: B B
authors.initials: BB
authors.lastname: Bauer
authors.forename: J E
authors.initials: JE
authors.lastname: Brown
authors.forename: D
authors.initials: D
authors.lastname: Carr
authors.forename: J
authors.initials: J
authors.lastname: Catino
authors.forename: C A
authors.initials: CA
authors.lastname: Evans
authors.forename: V
authors.initials: V
authors.lastname: Girijavallabhan
authors.forename: L
authors.initials: L
authors.lastname: Heimark
authors.forename: L
authors.initials: L
authors.lastname: James
authors.forename: S
authors.initials: S
authors.lastname: Liberles
authors.forename: C
authors.initials: C
authors.lastname: Nash
authors.forename: L
authors.initials: L
authors.lastname: Perkins
authors.forename: M M
authors.initials: MM
authors.lastname: Senior
authors.forename: A
authors.initials: A
authors.lastname: Tsarbopoulos
authors.forename: S E
authors.initials: SE
authors.lastname: Webber
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D016283:Proto-Oncogene Proteins p21(ras)