MI-63 and Bone-Neoplasms

We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a K(i) of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Bone Neoplasms; Cell Line, Tumor; Drug Design; HCT116 Cells; Humans; Indoles; Mice; Morpholines; Osteosarcoma; Piperazines; Proto-Oncogene Proteins c-mdm2; Rats; Spiro Compounds; Structure-Activity Relationship; Tumor Suppressor Protein p53