Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction.

Journal of medicinal chemistry

PubMedID: 25384157

Rew Y, Sun D, Yan X, Beck HP, Canon J, Chen A, Duquette J, Eksterowicz J, Fox BM, Fu J, Gonzalez AZ, Houze J, Huang X, Jiang M, Jin L, Li Y, Li Z, Ling Y, Lo MC, Long AM, McGee LR, McIntosh J, Oliner JD, Osgood T, Saiki AY, Shaffer P, Wang YC, Wortman S, Yakowec P, Ye Q, Yu D, Zhao X, Zhou J, Medina JC, Olson SH. Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction. J Med Chem. 2014;.
Structure-based rational design and extensive SAR led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of 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 an 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition = 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo anti-tumor 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.