Discovery of a novel class of highly potent inhibitors of the p53–MDM2 interaction by structure-based design starting from a conformational argument
Abstract
The p53-MDM2 interaction is an anticancer drug target under investigation in the clinic. Our compound NVP-CGM097 is one of the small molecule inhibitors of this protein-protein interaction currently evaluated in cancer patients. As part of our effort to identify new classes of p53-MDM2 inhibitors that could lead to additional clinical candidates, we report here the design of highly potent inhibitors having a pyrazolopyrrolidinone core structure. The conception of these new inhibitors originated in a consideration on the MDM2 bound conformation of the dihydroisoquinolinone class of inhibitors to which NVP-CGM097 belongs. This work forms the foundation of the discovery of HDM201, a second generation p53-MDM2 inhibitor that recently entered phase I clinical trial.
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NVP-HDM201 (siremadlin) is an imidazolpyrrolidone analog developed by Novartis that has demonstrated highly favorable in vivo properties as an orally effective and selective MDM2-p53 inhibitor.
“NVP-HDM201 (147), also known as siremadlin, is an imidazolpyrrolidone analog developed by Novartis that has demonstrated highly favorable in vivo properties as an orally effective and selective MDM2-p53 inhibitor and recently entered phase I clinical trials in cancer patients.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [394]
In preclinical studies, both once daily and once every three weeks dosing regimens of NVP-HDM201 showed comparable long-term efficacy.
“In preclinical studies, both once daily and once every three weeks dosing regimens showed comparable long-term efficacy.393,394”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [394]
NVP-HDM201 prevents p53 degradation by interfering with the interaction between human and mouse MDM2-p53, and has good pharmacokinetic and pharmacodynamic characteristics in animals, as well as good oral bioavailability.
“It prevents p53 degradation by interfering with the interaction between human and mouse MDM2-p53, and has good pharmacokinetic and pharmacodynamic characteristics in animals, as well as good oral bioavailability.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [394]
Compound 20 has improved binding ability to 0.13 nM and cell activity to 90 nM.
“which led to the discovery of Compound 20 with further improved binding ability to 0.13 nM and cell activity to 90 nM [75].”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [75]
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References 15 · Cited by 80
- Authors
- Furet, P., Masuya, K., Kallen, J., Stachyra-Valat, T., Ruetz, S., Guagnano, V., Holzer, P., Mah, R., Stutz, S., Vaupel, A., Chène, P., Jeay, S., & Schlapbach, A.
- Affiliations
- Novartis (Switzerland) (CH)
- Corresponding author
- Furet, Pascal
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 26
- Issue
- 19
- Pages
- 4837-4841
- ISSN
- 0960-894X (ISSN-L)
- OpenAlex
- W2513943644
- Cited by
- 80
- References
- 15
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 4 · 2023: 11 · 2022: 5 · 2021: 7 · 2020: 8 · 2019: 12 · 2018: 9 · 2017: 8 · 2016: 2
- FWCI
- 5.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- 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
- p53-MDM2 interaction, protein-protein interaction inhibitors, structure-based drug design, anticancer drug targets
- MeSH terms
- Molecular Conformation, Tumor Suppressor Protein p53, Crystallography, X-Ray, Fluorescence Resonance Energy Transfer, Proto-Oncogene Proteins c-mdm2, Drug Discovery
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