Phosphonate-containing inhibitors of tyrosine-specific protein kinases.
Tyrosine-specific protein kinases (TPK) are important signal transducing enzymes involved in normal cellular growth and differentiation and have been implicated in the etiology of a number of human neoplastic processes. Efforts to develop agents which inhibit the function of these enzymes by interfering with the binding of substrate have been limited by the lack of detailed three-dimensional structural data. Many inhibitors of substrate binding share a common styrene nucleus 1 which has been postulated to function as a conformationally constrained analogue of tyrosine. In an effort to develop high-affinity compounds based on this hypothesis, a number of derivatives were synthesized in which either methylphosphonate (4a-c) or (hydroxymethyl)phosphonate (3a-c) were appended to the aromatic 4-position of styrene-containing moieties. The intent of this approach was to prepare hydrolytically stable analogues which expressed additional enzyme recognition features present during the phosphorylation of tyrosine itself. None of the analogues showed inhibitory activity up to the maximum concentration tested (1000 microM) when assayed against autophosphorylation of A-431-derived epidermal growth factor receptor (EGFR) or p56lck (autophosphorylation and transphosphorylation of rabbit muscle enolase). Additionally, a series of naphthalene-based inhibitors including (1-naphthalenylhydroxymethyl)phosphonic acid (14), its known 2-positional isomer 16, and sulfonate (19, 20) and phosphate derivatives (17, 18) were also tested under similar conditions. Only (2-naphthalenyl-hydroxymethyl)phosphonic acid (16) showed activity (IC50 = 250 microM in EGFR, in agreement with the reported literature value). These results suggest that the interaction of styrene-based inhibitors with the substrate binding domain of TPKS may not occur in a manner analogous to the interaction of tyrosine with this domain.
Burke
T R
TR
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Li
Z H
ZH
Bolen
J B
JB
Marquez
V E
VE
D000818:Animals; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology; D010751:Phosphopyruvate Hydratase / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000138:chemical synthesis* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D063065:Organophosphonates; D013343:Styrenes; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D010751:Phosphopyruvate Hydratase