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 spc1Δ, at a minimal inhibitory concentration (MIC) of 3.76 μM. HWY 5069 also completely inhibited Spc1 kinase activity in vitro with an IC50 of 16.4 μM 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.
Bibliographical noteFunding Information:
HWY 5069 was provided by Hanwha Chemical Research and Development and has been patented (U.S. Patent 6,030,978). The authors would like to thank Drs. K. Gould, A. Albright, P. Fantes, P. Russell, J. Cooper, and D. Young for providing fission yeast strains and J. Jang in the lab for editing the manuscript. This work was supported by a grant from the 21C Frontier Microbial Genomics and Application Center Program, Ministry of Science & Technology (MG05-0203-1-0) of Republic of Korea and partly by the Yonsei University Research Fund of 2003. J.E.P. was supported by a Korea Research Foundation grant (KRF-2004-005-E00017), and H.-J.K. was supported by the Brain Korea 21 Project of 2004.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Drug Discovery
- Clinical Biochemistry