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An MMP13-Selective Inhibitor Delays Primary Tumor Growth and the Onset of Tumor-Associated Osteolytic Lesions in Experimental Models of Breast Cancer 1 1 1 1,2 3 3 Manisha Shah *, Dexing Huang , Tony Blick , Andrea Connor , Lawrence A. Reiter , Joel R. Hardink , 4 1 1,2 Conor C. Lynch , Mark Waltham , Erik W. Thompson 1 St. Vincent’s Institute of Medical Research, St. Vincent’s Hospital, Melbourne, Australia, 2 University of Melbourne Department of Surgery, St. Vincent’s Hospital, Melbourne, Australia, 3 Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut, United States of America, 4 H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America Abstract We investigated the effects of the matrix metalloproteinase 13 (MMP13)-selective inhibitor, 5-(4-{4-[4-(4-fluorophenyl)-1,3- oxazol-2-yl]phenoxy}phenoxy)-5-(2-methoxyethyl) pyrimidine-2,4,6(1H,3H,5H)-trione (Cmpd-1), on the primary tumor growth and breast cancer-associated bone remodeling using xenograft and syngeneic mouse models. We used human breast cancer MDA-MB-231 cells inoculated into the mammary fat pad and left ventricle of BALB/c Nu/Nu mice, respectively, and spontaneously metastasizing 4T1.2-Luc mouse mammary cells inoculated into mammary fat pad of BALB/c mice. In a prevention setting, treatment with Cmpd-1 markedly delayed the growth of primary tumors in both models, and reduced the onset and severity of osteolytic lesions in the MDA-MB-231 intracardiac model. Intervention treatment with Cmpd-1 on established MDA-MB-231 primary tumors also signif