Ras oncoprotein inhibitors: the discovery of potent, ras nucleotide exchange inhibitors and the structural determination of a drug-protein complex.
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.
Taveras
A G
AG
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Remiszewski
S W
SW
Doll
R J
RJ
Cesarz
D
D
Huang
E C
EC
Kirschmeier
P
P
Pramanik
B N
BN
Snow
M E
ME
Wang
Y S
YS
del Rosario
J D
JD
Vibulbhan
B
B
Bauer
B B
BB
Brown
J E
JE
Carr
D
D
Catino
J
J
Evans
C A
CA
Girijavallabhan
V
V
Heimark
L
L
James
L
L
Liberles
S
S
Nash
C
C
Perkins
L
L
Senior
M M
MM
Tsarbopoulos
A
A
Webber
S E
SE
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
D016283:Proto-Oncogene Proteins p21(ras)