An isoquinolinium derivative selectively inhibits MAPK Spc1 of the stress-activated MAPK cascade of Schizosaccharomyces pombe.
We have extended the search for selective inhibitors of the kinases of MAPK cascades by screening a derivative library of one of the isoquinoline rings of the protoberberine backbone. HWY 5069 inhibited the proliferation of wild-type and all mutants of Schizosaccharomyces pombe examined, except spc1Delta, at a minimal inhibitory concentration (MIC) of 3.76 microM. HWY 5069 also completely inhibited Spc1 kinase activity in vitro with an IC(50) of 16.4 microM as a competitive inhibitor of substrate binding. It was highly selective for Spc1 and did not affect the activity of other kinases in the MAPK cascades of fission yeast and mammals, including functional homologs of Spc1.
Kim
Hyun-Jun
HJ
Department of Biochemistry and Institute of Life Science and Biotechnology, College of Science, Yonsei University, Seoul 120-749, Korea.
Park
Jeong Eun
JE
Jin
Sangwook
S
Kim
Jung-Ho
JH
Song
Kiwon
K
D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012568:Schizosaccharomyces / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D013329:Structure-Activity Relationship; D013997:Time Factors
C514881:HWY 5069; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D020928:Mitogen-Activated Protein Kinases