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Discovery of AMG 232, a Potent, Selective, and Orally Bioavailable MDM2-p53 Inhibitor in Clinical Development.

Sun, D., Li, Z., Rew, Y., Gribble, M., Bartberger, M.D., Beck, H.P., Canon, J., Chen, A., Chen, X., Chow, D., Deignan, J., Duquette, J., Eksterowicz, J., Fisher, B., Fox, B.M., Fu, J., Gonzalez, A.Z., Gonzalez-Lopez De Turiso, F., Houze, J.B., Huang, X., Jiang, M., Jin, L., Kayser, F., Liu, J.J., Lo, M.C., Long, A.M., Lucas, B., McGee, L.R., McIntosh, J., Mihalic, J., Oliner, J.D., Osgood, T., Peterson, M.L., Roveto, P., Saiki, A.Y., Shaffer, P., Toteva, M., Wang, Y., Wang, Y.C., Wortman, S., Yakowec, P., Yan, X., Ye, Q., Yu, D., Yu, M., Zhao, X., Zhou, J., Zhu, J., Olson, S.H., Medina, J.C.

(2014) J Med Chem 57: 1454-1472

• PubMed: 24456472 Search on PubMed
• DOI: https://doi.org/10.1021/jm401753e
• Primary Citation of Related Structures:  
  4OAS


• PubMed Abstract: 
  

  We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).

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Organizational Affiliation: 

Departments of Therapeutic Discovery, ‡Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California, 94080, United States.