Bicyclic compounds as ring-constrained inhibitors of protein-tyrosine kinase p56lck.
A study was undertaken to prepare inhibitors of the lymphocyte protein-tyrosine kinase p56lck. Using the known p56lck inhibitor 3,4-dihydroxy-alpha-cyanocinnamamide (4) as a lead compound, bicyclic analogues were designed as conformationally constrained mimetics in which the phenyl ring and vinyl side chain of the cinnamamide are locked into a coplanar orientation. Such planarity was rationalized to be an important determinant for binding within a putative flat, cleftlike catalytic cavity. Bicyclic analogues were prepared using the naphthalene, quinoline, isoquinoline, and 2-iminochromene ring systems and examined for their ability to inhibit autophosphorylation of immunopurified p56lck. The most potent analogues were methyl 7,8-dihydroxyisoquinoline-3-carboxylate (12) (IC50 = 0.2 microM) and 7,8-dihydroxyisoquinoline-3-carboxamide (13) (IC50 = 0.5 microM). Inhibition by 12 was not competitive with respect to ATP. These compounds may represent important new structural motifs for the development of p56lck inhibitors.
Burke
T R
TR
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Lim
B
B
Marquez
V E
VE
Li
Z H
ZH
Bolen
J B
JB
Stefanova
I
I
Horak
I D
ID
D000255:Adenosine Triphosphate / Q000378:metabolism; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D015394:Molecular Structure; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000201:enzymology; D014407:Tumor Cells, Cultured
C080793:7,8-dihydroxyisoquinoline-3-carboxamide; D001643:Bridged Bicyclo Compounds; D007546:Isoquinolines; C080792:methyl 7,8-dihydroxyisoquinoline-3-carboxylate; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)