amg-232 and Colonic-Neoplasms

Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Colonic Neoplasms; Drug Discovery; Female; Humans; Mice; Mice, Nude; Models, Molecular; Molecular Structure; Protein Binding; Proto-Oncogene Proteins c-mdm2; Structure-Activity Relationship; Tumor Cells, Cultured; Tumor Suppressor Protein p53