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Rational design and binding mode duality of MDM2-p53 inhibitors.
Felix Gonzalez-Lopez de Turiso1, Daqing Sun, Yosup Rew
1Department of Therapeutic Discovery, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, USA.
Journal of Medicinal Chemistry
|April 20, 2013
Summary
Researchers developed novel morpholinone compounds that inhibit MDM2, a key protein in cancer. Compound 27 showed potent inhibition and induced a cancer-related gene in preclinical studies, indicating therapeutic potential.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Pharmacology
Background:
- MDM2 is a critical regulator of the p53 tumor suppressor protein.
- Inhibiting the MDM2-p53 interaction is a promising strategy for cancer therapy.
- Structure-based drug design can yield potent and selective inhibitors.
Purpose of the Study:
- To design and synthesize novel MDM2 inhibitors based on structural analysis.
- To optimize lead compounds for improved potency and drug-like properties.
- To evaluate the in vitro and in vivo efficacy of novel morpholinone derivatives.
Main Methods:
- Structure-based design and synthesis of tetrasubstituted morpholinones.
- Biochemical and cellular assays to determine inhibitory activity (IC50).
- Co-crystallography to elucidate binding modes.
- Pharmacokinetic profiling and in vivo pharmacodynamic studies in tumor-bearing mice.
Main Results:
- Synthesis of morpholinone 10 with an IC50 of 1.0 μM against MDM2.
- Discovery of optimized analogues 16 and 27 with distinct binding modes.
- Morpholinone 27 demonstrated potent inhibition (IC50 = 0.10 μM) and favorable pharmacokinetics.
- Oral administration of morpholinone 27 induced p21(WAF1) mRNA in a human tumor xenograft model.
Conclusions:
- Novel morpholinones targeting the MDM2-p53 interaction were successfully designed and synthesized.
- Morpholinone 27 represents a promising preclinical candidate for MDM2-targeted cancer therapy.
- Further investigation of morpholinone 27 in vivo is warranted based on PD findings.
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