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Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors
Abstract
As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.
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In the citing paper
“In wild-type p53 cells, NVP-CGM097 significantly induced the redistribution of p53 into the nucleus (IC50 = 0.224 μM).388”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [388]
In the citing paper
“NVP-CGM097 (145) is a highly effective and selective MDM2 inhibitor developed by Novartis.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [388]
In the citing paper
“It binds to the p53 binding site of MDM2 protein and disrupts the interaction between proteins, leading to the activation of the p53 pathway.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [388]
In the citing paper
“The cocrystal structure of NVP-CGM097 and MDM2 protein is shown in Fig. 14, which showed that the dihydroisoquinolinone scaffold is located in the middle of the MDM2 active pocket as a scaffold to connect the three key groups to occupy the three key active cavities of Leu26, Trp23 and Phe19.”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [68]
In the citing paper
“Finally, NVP-CGM097 was obtained by ammonia methylation of piperazinone to enhance its permeability, which showed good cell activity, metabolic stability and PK parameters [68].”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [68]
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Metadata
- Authors
- Holzer, P., Masuya, K., Furet, P., Kallen, J., Valat-Stachyra, T., Ferretti, S., Berghausen, J., Bouisset-Leonard, M., Buschmann, N., Pissot-Soldermann, C., Rynn, C., Ruetz, S., Stutz, S., Chène, P., Jeay, S., & Gessier, F.
- Affiliations
- Novartis Institutes for BioMedical Research (CH)
- Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland
- Corresponding author
- Holzer, Philipp
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-08-05
- Volume
- 58
- Issue
- 16
- Pages
- 6348-6358
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W1199549464
- Cited by
- 203
- References
- 26
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 18 · 2023: 25 · 2022: 18 · 2021: 34 · 2020: 20 · 2019: 19 · 2018: 22 · 2017: 11 · 2016: 12 · 2015: 2
- FWCI
- 6.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- MDM2 inhibitors, mechanism of action, binding mode, pharmacokinetics, pharmacodynamics, toxicity, anticancer drug discovery
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Isoquinolines, Piperazines, Structure-Activity Relationship, Tumor Suppressor Protein p53, Clinical Trials, Phase I as Topic, Xenograft Model Antitumor Assays, Cell Line, Tumor, Rats, Proto-Oncogene Proteins c-mdm2, Drug Discovery
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