1a-docosahexaenoyl mitomycin C: a novel inhibitor of protein tyrosine kinase.
A series of derivatives of mitomycin C conjugated with various fatty acids at position 1a was synthesized and the effect of these compounds on protein kinase activities was evaluated. 1a-Docosahexaenoyl mitomycin C (DMMC) selectively inhibited protein tyrosine kinase (PTK) activity in the postnuclear fraction of v-src-transformed NIH 3T3 cells although neither derivatives conjugated with other fatty acids or docosahexaenoic acid or mitomycin C did not. DMMC inhibited the activity of calmodulin-dependent kinase III and protein kinase A very weakly, and only barely affected protein kinase C activity. DMMC also attenuated autophosphorylation of immunoprecipitated p60v-src irreversibly. The addition of thiol compounds to the reaction mixture reversed the inhibition by DMMC, suggesting that some thiol moiety of PTK protein might be involved. DMMC also inhibited kinase activity of p210bcr-abl immunoprecipitated from the lysate of K562 cells. These results indicate that DMMC is a novel inhibitor of PTK.
Shikano
M
M
Department of Bioactive Molecules, National Institute of Infectious Diseases, Tokyo, Japan.
Onimura
K
K
Fukai
Y
Y
Hori
M
M
Fukazawa
H
H
Mizuno
S
S
Yazawa
K
K
Uehara
Y
Y
D016475:3T3 Cells; D000818:Animals; D002461:Cell Line, Transformed; D004281:Docosahexaenoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016391:Genes, src; D007700:Kinetics; D051379:Mice; D016685:Mitomycin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008937:Mitomycins; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D015688:Oncogene Protein pp60(v-src) / Q000096:biosynthesis / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C114019:1a-docosahexaenoyl mitomycin C; D004791:Enzyme Inhibitors; D008937:Mitomycins; D004281:Docosahexaenoic Acids; D016685:Mitomycin; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D015688:Oncogene Protein pp60(v-src)