The DOI matches its Crossref record; 25 of the 26 references it cites were found in a registry or an index.
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]
Citations
Cites
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WAF1, a potential mediator of p53 tumor suppression
El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B. (1993) · Cell · doi:10.1016/0092-8674(93)90500-p · Cited by 8,321
Lane, D. P. (1992) · Nature · doi:10.1038/358015a0 · Cited by 5,138
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206
The p53 pathway: positive and negative feedback loops
Harris, S. L., & Levine, A. J. (2005) · Oncogene · doi:10.1038/sj.onc.1208615 · Cited by 1,967
Kruse, J.-P., & Gu, W. (2009) · Cell · doi:10.1016/j.cell.2009.04.050 · Cited by 1,610
Physiochemical drug properties associated with in vivo toxicological outcomes
Hughes, J. D., Blagg, J., Price, D. A., Bailey, S., DeCrescenzo, G. A., Devraj, R. V., Ellsworth, E., Fobian, Y. M., Gibbs, M. E., Gilles, R. W., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.07.071 · Cited by 946
A General and Efficient Copper Catalyst for the Amidation of Aryl Halides
Klapars, A., Huang, X. S., & Buchwald, S. L. (2002) · Journal of the American Chemical Society · doi:10.1021/ja0260465 · Cited by 855
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BindingDB Entry 50010808: Medicinal Chemistry of Inhibiting RING-Type E3 Ubiquitin Ligases.
BindingDB (2021) · UC San Diego · doi:10.7270/q2qn6bbk
BindingDB Entry 50000524: Conformational control in structure-based drug design.
BindingDB (2019) · UC San Diego · doi:10.7270/q2tf00sv
BindingDB Entry 50003121: Role of p53 circuitry in tumorigenesis: A brief review.
BindingDB (2020) · UC San Diego · doi:10.7270/q28g8pc5
BindingDB (2019) · UC San Diego · doi:10.7270/q25q4zcf
BindingDB Entry 50013996: From High-Throughput Screening to Target Validation: Benzo[
BindingDB (2022) · UC San Diego · doi:10.7270/q2j106zz
BindingDB (2020) · UC San Diego · doi:10.7270/q2c82d0h
BindingDB (2019) · UC San Diego · doi:10.7270/q2jw8h51
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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