We previously identified a cellular target of a cell cycle inhibitor HBC as Ca2+/calmodulin (Ca2+/CaM) through chemical genetics approach. Using the mechanism-based drug design, we developed a new Ca2+/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-pip erazin-1-yl)-methanone (referred as HBCP), binds to Ca2+/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 Ca2+/CaM antagonist and can be applied for CaM related therapeutic uses. (c) 2007 Published by Elsevier Inc.