3424 Epothilones represent a novel class of natural products which stabilize microtubules. Some of these natural products as well as their synthetic analogs have shown promising activity in experimental preclinical cancer studies and in cancer patients. Based on a broad fully synthetic drug optimization program with more than 350 synthesized analogs, we have developed ZK-EPO, a new derivative with outstanding preclinical efficacy. In contrast to other tubulin targeting drugs (i.e.paclitaxel), ZK-EPO is rapidly taken up by the tumor cells and preferentially accumulates in the cell nucleus. ZK-EPO inhibits the growth of a wide range of different human cancer cell lines, and, unlike paclitaxel, also suppresses the growth of cell lines that over-express P-glycoprotein at sub-nanomolar concentrations. We have shown that this epothilone is not recognized by cellular efflux mechanisms. Dose response studies with in vivo xenograft cancer models either sensitive or intrinsically resistant to paclitaxel demonstrated strong antiproliferative activity and a large therapeutic window of ZK-EPO. This broad preclinical activity spectrum provides strong evidence, that the novel epothilone analogue ZK-EPO may have antitumor efficacy in a variety of rather chemoresistant cancer indications and the compound is therefore currently being investigated in patients with different solid tumors. Breast cancer frequently metastasizes to the bones. Treatment of bone metastases is still a challange in the treatment of breast cancer. We have evaluated ZK-EPO in a breast cancer metastasis model in nude mice for palliative and adjuvant treatment. Results from these experiments demonstrated that ZK-EPO is active against bone metastases.