Structure-based design of novel, urea-containing FKBP12 inhibitors.
The structure-based design and subsequent chemical synthesis of novel, urea-containing FKBP12 inhibitors are described. These compounds are shown to disrupt the cis-trans peptidylprolyl isomerase activity of FKBP12 with inhibition constants (Ki,app) approaching 0.10 microM. Analyses of several X-ray crystal structures of FKBP12-urea complexes demonstrate that the urea-containing inhibitors associate with FKBP12 in a manner that is similar to, but significantly different from, that observed for the natural product FK506.
Dragovich
P S
PS
Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA.
Barker
J E
JE
French
J
J
Imbacuan
M
M
Kalish
V J
VJ
Kissinger
C R
CR
Knighton
D R
DR
Lewis
C T
CT
Moomaw
E W
EW
Parge
H E
HE
Pelletier
L A
LA
Prins
T J
TJ
Showalter
R E
RE
Tatlock
J H
JH
Tucker
K D
KD
Villafranca
J E
JE
D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000737:chemistry; D022021:Tacrolimus Binding Proteins; D014508:Urea / Q000032:analysis*
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D014508:Urea; D000591:Amino Acid Isomerases; D022021:Tacrolimus Binding Proteins; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus