Structure-based design of novel nonpeptide inhibitors of the Src SH2 domain:phosphotyrosine mimetics exploiting multifunctional group replacement chemistry.
A series of novel nonpeptide inhibitors of the pp60(c-Src) (Src) SH2 domain is described that exploit multifunctional group replacement of the phenylphosphate moiety of phosphotyrosine (pTyr). Relative to an x-ray structure of citrate complexed to the pTyr binding site of the Src SH2 domain, these nonpeptide ligands illustrate the systematic replacement of the phosphate group by multiple nonhydrolyzable, mono- or dianionic functionalities. Specifically, several phenylalanine (Phe) analogs incorporating key 4' and 3' substituents were synthesized and incorporated into a bicyclic benzamide template previously reported (W. C. Shakespeare et al., Proceedings of the National Academy of Science USA, 2000, Vol. 97, pp. 9373-9378). These pTyr mimetics included 4',3'-diphosphono-Phe (Dpp), 4',3'-dicarboxymethyloxy-Phe (Dcp), and 4'-phosphono-3'-carboxymethyloxy-Phe (Cpp). Noteworthy were nonpeptide inhibitors 8-11 that were 5- to 10-fold more potent than the cognate tetrapeptide ligand Ac-pTyr-Glu-Glu-Ile-NH(2) in binding to the Src SH2 domain.
ARIAD Pharmaceuticals, 26 Landsdowne Street, Cambridge, MA 02139-4234, USA.
Raji
R
Sundaramoorthi
Noriyuki
N
Kawahata
Michael G
MG
Yang
William C
WC
Shakespeare
Chester A
CA
Metcalf
Yihan
Y
Wang
Taylor
T
Merry
Charles J
CJ
Eyermann
Regine S
RS
Bohacek
Surinder
S
Narula
David C
DC
Dalgarno
Tomi K
TK
Sawyer
D001665:Binding Sites; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D019000:Phosphotyrosine / Q000737:chemistry*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D018909:src Homology Domains
D004791:Enzyme Inhibitors; D010455:Peptides; D019000:Phosphotyrosine; D016392:Proto-Oncogene Proteins pp60(c-src)