A novel phosphotyrosine mimetic 4'-carboxymethyloxy-3'-phosphonophenylalanine (Cpp): exploitation in the design of nonpeptide inhibitors of pp60(Src) SH2 domain.
The novel phosphotyrosine (pTyr) mimetic 4'-carboxymethyloxy-3'-phosphonophenylalanine (Cpp) has been designed and incorporated into a series of nonpeptide inhibitors of the SH2 domain of pp60(c-Src) (Src) tyrosine kinase. A 2.2 A X-ray crystal structure of 1a bound to a mutant form of Lck SH2 domain provides insight regarding the structure-activity relationships and supports the design concept of this new pTyr mimetic.
Kawahata
N
N
ARIAD Pharmaceuticals, Inc., Cambridge, MA 02139-4234, USA.
Yang
M G
MG
Luke
G P
GP
Shakespeare
W C
WC
Sundaramoorthi
R
R
Wang
Y
Y
Johnson
D
D
Merry
T
T
Violette
S
S
Guan
W
W
Bartlett
C
C
Smith
J
J
Hatada
M
M
Lu
X
X
Dalgarno
D C
DC
Eyermann
C J
CJ
Bohacek
R S
RS
Sawyer
T K
TK
D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D001862:Bone Resorption; D018360:Crystallography, X-Ray; D003804:Dentin / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D009154:Mutation; D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D019000:Phosphotyrosine / Q000737:chemistry*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011817:Rabbits; D013329:Structure-Activity Relationship; D018909:src Homology Domains / Q000187:drug effects*
C442382:4-(2-acetamido-3-(1-(3-carbamoyl-4-(cyclohexylmethoxy)phenyl)ethylamino)-3-oxopropyl)-2-(carboxymethoxy)benzenephosphonic acid; D001549:Benzamides; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D019000:Phosphotyrosine; D016392:Proto-Oncogene Proteins pp60(c-src)