Cancer is a disease of unscheduled cell division and many anticancer drugs target the cell cycle to inhibit the proliferation of cancer cells. We conducted a screen for new anticancer drugs that induce cell cycle arrest using a small compound library. From this screen, we identified 2-(3-methyl-thiophen-2-yl)-4-(3,4-dioxybenzene) thiazole (MTBT), which causes accumulation of cancer cells with 4N DNA content and inhibits colony formation of several cancer cell lines. We further showed that the treatment of cancer cells with this compound for a longer time period leads to apoptosis, as indicated by the presence of cells with a sub-G1 peak and the appearance apoptotic markers. The increased phosphorylation of serine 10 on histone H3 in MTBT-treated cancer cells suggests cell cycle arrest in the M-phase. Strikingly, MTBT-induced cell cycle arrest and enhanced H3 (Ser10) phosphorylation are abrogated by the pretreatment with SB203580, a specific inhibitor of mitogen-activated protein kinase p38. Moreover, treatment of cancer cells with MTBT induces the phosphorylation of p38, indicative of p38 activation. Together, we have identified a new compound that inhibits cancer cell proliferation, which is likely a consequence of p38 activation.