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Thus, inhibiting NOTCH1 activity represents a potential therapeutic opportunity for this disease. Using gene expression\u2010based screening, we identified the calcium channel modulator bepridil as a new NOTCH1 pathway inhibitor. In primary CLL cells, bepridil induced selective apoptosis even in the presence of the protective stroma. Cytotoxic effects of bepridil were independent of <jats:italic>NOTCH1<\/jats:italic> mutation and other prognostic markers. The antitumor efficacy of bepridil was associated with inhibition of NOTCH1 activity through a decrement in trans\u2010membrane and activated NOTCH1 protein levels with unchanged NOTCH2 protein levels. In a CLL xenotransplant model, bepridil significantly reduced the percentage of leukemic cells infiltrating the spleen via enhanced apoptosis and decreased NOTCH1 activation. In conclusion, we report <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> anti\u2010leukemic activity of bepridil associated with inhibition of the NOTCH1 pathway in CLL. 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