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J Med Chem. 2013 May 23;56(10):4053-70. doi: 10.1021/jm400293z. Epub 2013 May 6.

Rational design and binding mode duality of MDM2-p53 inhibitors.

Author information

1
Department of Therapeutic Discovery, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, USA.

Abstract

Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 μM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 μM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAF1) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.

PMID:
23597064
DOI:
10.1021/jm400293z
[Indexed for MEDLINE]

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