Cited by 215Cancer-related Molecular PathwaysCancer Mechanisms and TherapyPI3K/AKT/mTOR signaling in cancer

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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

Holzer, Philipp, Masuya, Keiichi, Furet, Pascal, Kallen, Joerg, Valat-Stachyra, Therese, Ferretti, Stéphane, Berghausen, Joerg, Bouisset-Leonard, Michèle, Buschmann, Nicole, Pissot-Soldermann, Carole, Rynn, Caroline, Ruetz, Stephan, Stutz, Stefan, Chène, Patrick, Jeay, Sébastien, Gessier, Francois·2015·Journal of Medicinal Chemistry

DOI 10.1021/acs.jmedchem.5b00810

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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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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
ORCID: Holzer, Philipp
Furet, Pascal
Kallen, Joerg
Ferretti, Stéphane
Rynn, Caroline
Jeay, Sébastien
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
DOI: 10.1021/acs.jmedchem.5b00810
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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Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors

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