Development of a new Ca2+/calmodulin antagonist and its anti-proliferative activity against colorectal cancer cells.
We previously identified a cellular target of a cell cycle inhibitor HBC as Ca(2+)/calmodulin (Ca(2+)/CaM) through chemical genetics approach. Using the mechanism-based drug design, we developed a new Ca(2+)/CaM antagonists based on the structure of HBC. The compound, (4-{3,5-bis-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-4,5-dihydro-pyrazol-1-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone (referred as HBCP), binds to Ca(2+)/CaM in vitro and inhibits the proliferation of HCT15 colon cancer cells. HBCP induced sustained phosphorylation of ERK1/2 and subsequently activated p21(WAF1) expression in HCT15 cells. Moreover, HBCP reversibly induced the G(0)/G(1) cell cycle arrest in the cells. These data demonstrate that HBCP is a new potent Ca(2+)/CaM antagonist and can be applied for CaM related therapeutic uses.
Shim
Joong Sup
JS
Chemical Genomics Laboratory, Department of Biotechnology, College of Engineering, Yonsei University, Seoul 120-749, Republic of Korea.
Lee
Jiyong
J
Kim
Kyung Noo
KN
Kwon
Ho Jeong
HJ
D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
C521695:(4-(3,5-bis-(2-(4-hydroxy-3-methoxy-phenyl)vinyl)-4,5-dihydro-pyrazol-1-yl)-phenyl)-(4-methyl-piperazin-1-yl)methanone; C493956:CDKN1A protein, human; D002147:Calmodulin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010879:Piperazines; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium