Discovery of a Small Molecule MDM2 Inhibitor (AMG 232) for Treating Cancer
Abstract
We recently reported the discovery of AMG 232 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 protein-protein interaction. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer. This article provides an overview of its discovery from the de novo design of the piperidinone series to the structure-activity studies leading to the identification of 1. In addition, this article also describes the preclinical pharmacology and pharmacokinetics of 1, along with its drug metabolism and safety assessment.
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AMG-232 is a potent and highly selective oral piperidone inhibitor of MDM2-p53 interaction, with an IC50 of 0.6 nM and MDM2-binding Kd of 0.045 nM.
“AMG-232 (144) is a potent and highly selective oral piperidone inhibitor of MDM2-p53 interaction, with an IC50 of 0.6 nM and MDM2-binding Kd of 0.045 nM.383,384”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [384]
In the SJSA-1 osteosarcoma model, AMG232 has obvious anti-tumor activity and significantly promotes tumor regression without obvious toxicity or side effects.
“In the SJSA-1 osteosarcoma model, its anti-tumor activity was obvious, and it could significantly promote tumor regression without obvious toxicity or side effects [54, 55].”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [54]
AMG232 has low internal clearance rates in human hepatocytes and rats.
“low internal clearance rates in human hepatocytes and rats”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [54]
AMG232 has low inhibitory activities against CYP, CYP3A4 and PXR.
“low inhibitory activities against CYP, CYP3A4 and PXR”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [54]
AMG232 has better PK parameters in rhesus monkeys.
“simple structural optimization was carried out to obtain AMG232 [54], which had better PK parameters in rhesus monkeys”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [54]
AMG232 has 2500 times higher selectivity for tumor cells with high expression of wild-type p53 than for p53 knockout tumor cells.
“2500 times higher selectivity for tumor cells with high expression of wild-type p53 than that for p53 knockout tumor cells”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [54]
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- Authors
- Rew, Y., & Sun, D.
- Affiliations
- Amgen (United States) (US)
- Corresponding author
- Rew, Yosup
- Sun, Daqing
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2014-07-09
- Volume
- 57
- Issue
- 15
- Pages
- 6332-6341
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2313406933
- Cited by
- 125
- References
- 34
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 20 · 2023: 12 · 2022: 11 · 2021: 7 · 2020: 5 · 2019: 6 · 2018: 8 · 2017: 8 · 2016: 10 · 2015: 7 · 2014: 3 · 2013: 1
- Type
- other
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- MDM2 inhibitors, piperidinone, p53-MDM2 interaction, p53, anticancer drug discovery, structure-activity relationship, de novo design, pharmacokinetics, drug metabolism, drug safety, clinical trials
- MeSH terms
- Acetates, Animals, Antineoplastic Agents, Binding Sites, Humans, Models, Molecular, Piperidones, Protein Binding, Protein Conformation, Structure-Activity Relationship, Proto-Oncogene Proteins c-mdm2
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