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.