Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction.
J Med Chem
; 57(24): 10499-511, 2014 Dec 26.
Article
in En
| MEDLINE
| ID: mdl-25384157
ABSTRACT
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.
Full text:
1
Database:
MEDLINE
Main subject:
Protein Binding
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Tumor Suppressor Protein p53
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Colonic Neoplasms
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Cell Proliferation
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Proto-Oncogene Proteins c-mdm2
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Drug Discovery
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Antineoplastic Agents
Limits:
Animals
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Female
/
Humans
Language:
En
Year:
2014
Type:
Article