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However, these drugs have limited oral absorption, tumor cell entry and activity, and cause bone side effects. The potencies of phosphorylated antiviral drugs have been increased by administering them as prodrugs, in which the negative charges on the phosphate moieties are masked to make them lipophilic. We synthesized heterocyclic bisphosphonate (BP) prodrugs in which the phosphonate moieties are derivatized with pivaloyloxymethyl (pivoxil) groups and that lack the hydroxy \u201cbone hook\u201d on the geminal carbon. When the lipophilic BP prodrugs enter tumor cells, they are converted into their active forms by intracellular esterases. The most active BP prodrug, tetrakispivaloyloxymethyl 2\u2010(thiazole\u20102\u2010ylamino)ethylidene\u20101,1\u2010bisphosphonate (<jats:bold>7<\/jats:bold>), was found to potently inhibit the in\u2005vitro growth of a variety of tumor cell lines, especially hematopoietic cells, at nanomolar concentrations. Consistent with this fact, compound <jats:bold>7<\/jats:bold> inhibited the prenylation of the RAP1A small GTPase signaling protein at concentrations as low as 1\u201310\u2005n<jats:sc>m<\/jats:sc>. In preclinical studies, <jats:bold>7<\/jats:bold> slowed the growth of human bladder cancer cells in an immunodeficient mouse model. Thus, <jats:bold>7<\/jats:bold> is significantly more active than zoledronic acid, the most active FDA\u2010approved BP, and a potential anticancer therapeutic.<\/jats:p>","DOI":"10.1002\/cmdc.201600465","type":"journal-article","created":{"date-parts":[[2016,10,27]],"date-time":"2016-10-27T06:06:43Z","timestamp":1477548403000},"page":"2656-2663","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Targeting Cancer Cells with a Bisphosphonate Prodrug"],"prefix":"10.1002","volume":"11","author":[{"given":"Kenji","family":"Matsumoto","sequence":"first","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics Department of Immunology and Cell Biology Graduate School ofMedicine Kyoto University  Kyoto 606-8501 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Center for Innovation in 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